Left Atrial Mechanics Following Preeclamptic Pregnancy.

BACKGROUND: Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension and/or cardiac dysfunction. METHODS: In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. RESULTS: At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). CONCLUSIONS: LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

An altered gut microbiome in pre-eclampsia: cause or consequence.

Hypertensive disorders of pregnancy, including pre-eclampsia, are a leading cause of serious and debilitating complications that affect both the mother and the fetus. Despite the occurrence and the health implications of these disorders there is still relatively limited evidence on the molecular underpinnings of the pathophysiology. An area that has come to the fore with regard to its influence on health and disease is the microbiome. While there are several microbiome niches on and within the body, the distal end of the gut harbors the largest of these impacting on many different systems of the body including the central nervous system, the immune system, and the reproductive system. While the role of the microbiome in hypertensive disorders, including pre-eclampsia, has not been fully elucidated some studies have indicated that several of the symptoms of these disorders are linked to an altered gut microbiome. In this review, we examine both pre-eclampsia and microbiome literature to summarize the current knowledge on whether the microbiome drives the symptoms of pre-eclampsia or if the aberrant microbiome is a consequence of this condition. Despite the paucity of studies, obvious gut microbiome changes have been noted in women with pre-eclampsia and the individual symptoms associated with the condition. Yet further research is required to fully elucidate the role of the microbiome and the significance it plays in the development of the symptoms. Regardless of this, the literature highlights the potential for a microbiome targeted intervention such as dietary changes or prebiotic and probiotics to reduce the impact of some aspects of these disorders.

The Association between Threatened Miscarriage and Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Offspring by Age 14 Years.

OBJECTIVE: To examine the association between threatened miscarriage, and neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring by age 14 years. METHODS: We used data from the Millennium Cohort Study, a nationally representative longitudinal study of children born in the UK. Data on threatened miscarriage and potential confounders were maternal-reported and collected at 9 months postpartum. Data on ASD and ADHD were based on maternal-reported doctor diagnoses and collected when children were aged 5, 7, 11 and 14 years. A diagnosis of ASD or ADHD was assumed if parents reported ASD or ADHD at age 5, 7, 11 or 14 years. Crude and adjusted logistic regression examined threatened miscarriage and ASD and ADHD relationship, adjusting for several sociodemographic, maternal and lifestyle factors. RESULTS: A total of 18,294 singleton babies were included at baseline, and 1,104 (6.0%) women experienced a threatened miscarriage during their pregnancy. Adjusted results suggested an association between threatened miscarriage and ASD (OR: 1.55, 95% CI 1.15, 2.08), and ADHD (OR: 1.51, 95% CI 1.09, 2.10) by age 14 years. E-values for threatened miscarriage and ASD were 2.47, while the lower limits of the 95% CI were 1.57. E-values for threatened miscarriage and ADHD were 2.39, while the corresponding lower limits of the 95% CI were 1.40. CONCLUSION: Threatened miscarriage was associated with an increased likelihood of ASD and ADHD by the age of 14 years, however, residual confounding cannot be ruled out. Placental pathology may be a potential mechanism for the observed associations.

Hypertensive disorders of pregnancy and the risk of maternal dementia: a systematic review and meta-analysis.

OBJECTIVE: Hypertensive disorders of pregnancy, including preeclampsia, are associated with an increased risk for maternal cardiovascular disease, stroke, and chronic kidney disease. However, their association with subsequent maternal dementia or cognitive impairment is less well understood. This study aimed to review and synthesize the published literature on hypertensive disorders of pregnancy and the subsequent risk for maternal dementia or cognitive impairment. DATA SOURCES: PubMed, Web of Science, Pyschinfo, and CINAHL were searched from database inception until July 31, 2022, for observational studies of hypertensive disorders of pregnancy and maternal dementia or cognitive impairment. STUDY ELIGIBILITY CRITERIA: Selected studies included the following: a population of pregnant women, exposure to a hypertensive disorder of pregnancy of interest, and at least 1 primary outcome (dementia) or secondary outcome (cognitive impairment). Two reviewers were involved in study selection. METHODS: We followed the Meta-analyses of Observational Studies in Epidemiology guidelines throughout. Random-effects meta-analyses were used to calculate the overall pooled estimates. Bias was assessed using an adapted version of the validated Newcastle-Ottawa Quality Assessment tool. RESULTS: A total of 25 eligible studies were identified and included 2,501,673 women. Preeclampsia was associated with a significantly increased risk for vascular dementia (adjusted hazard ratio, 1.89; 95% confidence interval, 1.47-2.43), whereas no clear association was noted between preeclampsia and Alzheimer's disease (adjusted hazard ratio, 1.27; 95% confidence interval, 0.95-1.70), nor between preeclampsia and any (undifferentiated) dementia (adjusted hazard ratio, 1.18; 95% confidence interval, 0.95-1.47). However, in an analysis restricted to women aged 65 years and older, preeclampsia was associated with an increased risk for Alzheimer's disease (adjusted hazard ratio, 1.92; 95% confidence interval, 1.35-2.73) and any dementia (adjusted hazard ratio, 1.87; 95% confidence interval, 1.21-2.91). CONCLUSION: Women whose pregnancies were complicated by preeclampsia seem to be at a substantially increased future risk for vascular dementia. The longer-term risks among these women with regards to Alzheimer's disease and other forms of dementia are less clear.

Defective Visceral Adipose Tissue Adaptation in Gestational Diabetes Mellitus.

CONTEXT: Gestational diabetes mellitus (GDM) is a complex obstetric condition affecting localized glucose metabolism, resulting in systemic metabolic dysfunction. OBJECTIVE: This cross-sectional study aimed to explore visceral adipose tissue (VAT) as an integral contributor to GDM, focusing on elucidating the specific contribution of obesity and GDM pathology to maternal outcomes. METHODS: Fifty-six nulliparous pregnant women were recruited, including normal glucose tolerant (NGT) (n = 30) and GDM (n = 26) participants. Participants were subgrouped as nonobese (BMI <30 kg/m2) or obese (BMI ≥30 kg/m2). Metabolic markers in circulation, VAT, and placenta were determined. Morphological analysis of VAT and immunoblotting of the insulin signaling cascade were performed. RESULTS: GDM participants demonstrated hyperinsulinemia and elevated homeostatic model assessment for insulin resistance (HOMA-IR) scores relative to NGT participants. The GDM-obese subgroup had significant VAT adipocyte hypoplasia relative to NGT-nonobese tissue. GDM-obese VAT had significantly lower insulin receptor substrate (IRS)-2 expression, with elevated ser312 phosphorylation of IRS-1, relative to NGT-nonobese. GDM-obese participants had significantly elevated circulating leptin levels and placental adipsin secretion, while GDM-nonobese participants had elevated circulating adipsin levels with reduced placental adiponectin secretion. CONCLUSION: These findings suggest that GDM-obese pregnancy is specifically characterized by inadequate VAT remodeling and dysfunctional molecular signaling, which contribute to insulin resistance and hinder metabolic health.

L-ergothioneine reduces mitochondrial-driven NLRP3 activation in gestational diabetes mellitus.

BACKGROUND: Maternal hyperglycaemia has a significant impact on placental metabolism and mitochondrial function. The NLRP3 inflammasome is responsive to endogenous signals of mitochondrial dysfunction. We tested our hypothesis that mitochondrial dysfunction orchestrates activation of the NLRP3 inflammasome and contributes to inflammation in gestational diabetes mellitus (GDM). METHODS: Fasting blood, omental and placental tissue were collected on the day of caesarean section from nulliparous women with normal glucose tolerant (NGT) (n = 30) and GDM (n = 27) pregnancies. Cell-free mitochondrial DNA (cf-mtDNA) copy number was quantified by real-time PCR. M1-like (CD14+CD86+CD206-) and M2-like (CD14+CD86+CD206+) macrophage populations were characterized by flow cytometry. Immunoblotting for protein expression of NLRP3, ASC and caspase-1 was performed in maternal BMI and age-matched tissue samples. IL-1ß and IL-18 were measured by multiplex ELISA. Placental explants from GDM participants were cultured for 24 h with 1 mM L-ergothioneine (antioxidant) and 1 µM MCC950 (NLRP3 inhibitor). RESULTS: Cf-mtDNA copy numbers were significantly higher in GDM compared to NGT participants (p = 0.002). Placental populations of CD14+ (p = 0.02) and CD14+CD86+CD206- (p = 0.03) macrophages produced significantly increased levels of mitochondrial superoxide in GDM compared to NGT participants. Placental production of IL-18 (p = 0.04) was significantly increased in GDM. This increase in placental IL-18 was attenuated by treatment with 1 µM MCC950 (p = 0.0005), and 1 mM L-ergothioneine (p = 0.007). CONCLUSION: Placental inflammation is significantly increased in women with GDM. Furthermore, this increase may be initiated by elevated production of mitochondrial superoxide by macrophage subpopulations and orchestrated by the NLRP3 inflammasome. The mitochondrial antioxidant, L-ergothioneine, ameliorates NLRP3-induced placental inflammation in GDM, identifying a potential therapeutic role.

Prenatal maternal cortisol, stress and anxiety, and childhood obesity at 5 years: a nested case-control study.

BACKGROUND: Paediatric obesity is a global public health issue. Prenatal maternal mental health is potentially implicated in the development of childhood obesity. This study examined associations between prenatal maternal cortisol, self-reported stress, anxiety and depression in the second trimester, and childhood overweight and obesity at 5 years of age. METHODS: A nested case-control study was conducted using data from the Irish prospective longitudinal birth cohort SCOPE BASELINE. Cases were children with overweight or obesity, operationalised as having a BMI z-score above +2 standard deviations. Controls were children with a BMI z-score between -0.5 and 0.5 standard deviations at 5 years of age. Two to one matching by sex was conducted. Thirty-eight cases and 83 sex-matched controls were included. Maternal serum cortisol concentration and self-reported stress, anxiety and depression were measured at 15 ± 1 and 20 ± 1 weeks gestation. Conditional logistic regression analyses were conducted to examine associations between prenatal maternal cortisol and self-reported stress, anxiety and depression, and childhood overweight and obesity. RESULTS: Despite some evidence for associations between anxiety and depression, and child BMI z-scores in univariate analyses, adjusted models indicated no associations between prenatal maternal stress (OR: 1.02, 95% CI: 0.94-1.12), anxiety (OR: 1.03, 95% CI: 0.97-1.09), depression (OR: 1.04, 95% CI: 0.91-1.19), or cortisol concentration (OR: 0.99, 95% CI: 0.99-1.00) and child BMI z-score. CONCLUSION: Our findings do not provide support for associations between foetal exposure during the second trimester of pregnancy and maternal cortisol, stress and anxiety, and childhood overweight or obesity at 5 years of age.

Pregnancy and birth complications associations with long-term adverse maternal mental health outcomes: a systematic review and meta-analysis protocol.

Background: Existing studies have established an association between pregnancy, birth complications, and mental health in the first few weeks postpartum. However, there is no clear understanding of whether pregnancy and birth complications increase the risk of adverse maternal mental outcomes in the longer term. Research on maternal adverse mental health outcomes following pregnancy and birth complications beyond 12 months postpartum is scarce, and findings are inconsistent. Objective: This systematic review and meta-analysis will examine the available evidence on the association between pregnancy and birth complications and long-term adverse maternal mental health outcomes. Methods and analysis: We will include cohort, cross-sectional, and case-control studies in which a diagnosis of pregnancy and/or birth complication (preeclampsia, pregnancy loss, caesarean section, preterm birth, perineal laceration, neonatal intensive care unit admission, major obstetric haemorrhage, and birth injury/trauma) was reported and maternal mental disorders (depression, anxiety disorders, bipolar disorders, psychosis, and schizophrenia) after 12 months postpartum were the outcomes. A systematic search of PubMed, Embase, CINAHL, PsycINFO, and Web of Science will be conducted following a detailed search strategy until August 2022. Three authors will independently review titles and abstracts of all eligible studies, extract data using pre-defined standardised data extraction and assess the quality of each study using the Newcastle-Ottawa Scale. We will use random-effects meta-analysis for each exposure and outcome variable to calculate overall pooled estimates using the generic inverse variance method. This systematic review will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Ethical consideration: The proposed systematic review and meta-analysis is based on published data; ethics approval is not required. The results will be presented at scientific meetings and publish in a peer-reviewed journal. PROSPERO registration: CRD42022359017.

Association between socioeconomic status with pregnancy and neonatal outcomes: An international multicenter cohort.

INTRODUCTION: Previous evidence examining the association between socioeconomic status and pregnancy complications are conflicted and often limited to using area-based measures of socioeconomic status. In this study, we aimed to examine the association between individual-level socioeconomic factors and a wide range of adverse pregnancy and neonatal outcomes using data from the IMPROvED birth cohort conducted in Sweden, the Netherlands and Republic of Ireland. MATERIAL AND METHODS: The study cohort consisted of women who participated in the IMPROvED birth cohort between 2013 and 2017. Data on socioeconomic factors were self-reported and obtained at 15 weeks' gestation, and included level of education, employment status, relationship status, and income. Data on pregnancy and neonatal outcomes included gestational hypertension, pre-eclampsia, gestational diabetes mellitus, emergency cesarean section, preterm birth, post term delivery, small for gestational age and Apgar score at 1 min. These data were obtained within 72 h following delivery and confirmed using medical records. Multivariable logistic regression examined the association between each socioeconomic variable and each outcome separately adjusting for maternal age, maternal body mass index, maternal smoking, maternal alcohol consumption and cohort center. We also examined the effect of exposure to any ≥2 risk factors compared to none. RESULTS: A total of 2879 participants were included. Adjusted results suggested that those with less than third level of education had an increased odds of gestational hypertension (OR: 1.74, 95% CI: 1.23-2.46), while those on a middle level of income had a reduced odds of emergency cesarean section (OR: 0.59, 95% CI: 0.42-0.84). No significant associations were observed between socioeconomic variables and neonatal outcomes. Exposure to any ≥2 socioeconomic risk factors was associated with an increased risk of preterm birth (OR: 1.75, 95% CI: 1.06-2.89). CONCLUSIONS: We did not find strong evidence of associations between individual-level socioeconomic factors and pregnancy and neonatal outcomes in high-income settings overall, with only few significant associations observed among pregnancy outcomes.

Association Between Chronic Hypertension and the Risk of 12 Cardiovascular Diseases Among Parous Women: The Role of Adverse Pregnancy Outcomes.

BACKGROUND: Evidence on the association between chronic hypertension and the risk of cardiovascular disease (CVD) in mothers with adverse pregnancy outcomes (APOs) is limited. We investigated the association between chronic hypertension and risk of CVD, considering the role of APOs. METHODS: We used linked electronic health records in the CALIBER platform to define a UK cohort of women with recorded births between 1997 and 2016. We conducted multivariable Cox regression to estimate the association between chronic hypertension, with and without APOs, and 12 subsequent CVD events. RESULTS: The study cohort comprised 1 784 247 births (1.2 million women); of these 12 698 (0.71%) records had chronic hypertension, and 16 499 women had incident CVD during follow-up, of which 66% occurred in women under 40 years. Chronic hypertension (versus no chronic hypertension) was associated with a 2-fold higher risk of first subsequent CVD (adjusted hazard ratios, 2.22 [95% CI, 2.03-2.42]). Compared to normotensive women without APOs, the associations were the strongest in women with chronic hypertension and APOs across the 12 CVD outcomes, varying from 9.65 (5.96-15.6) for heart failure to 2.66 (2.17-3.26) for stable angina. In women with chronic hypertension without APOs, adjusted hazard ratios varied from 5.25 (3.47-7.94) for subarachnoid hemorrhage to 1.26 (0.59-2.67) for peripheral arterial disease. In women with APOs, but without chronic hypertension, adjusted hazard ratios varied from 3.27 (2.48-4.31) for intracerebral hemorrhage to 1.33 (1.26-1.41) for stable angina. CONCLUSIONS: We found strong associations between chronic hypertension and the risk of premature CVD, with greater risk in women who additionally had APOs. Intervention programs focused on these groups might lower their risk of subsequent CVD.

Hypertensive disorders of pregnancy and long-term risk of maternal stroke-a systematic review and meta-analysis.

OBJECTIVE: Hypertensive disorders of pregnancy are associated with a long-term risk for cardiovascular disease among parous patients later in life. However, relatively little is known about whether hypertensive disorders of pregnancy are associated with an increased risk for ischemic stroke or hemorrhagic stroke in later life. This systematic review aimed to synthesize the available literature on the association between hypertensive disorders of pregnancy and the long-term risk for maternal stroke. DATA SOURCES: PubMed, Web of Science, and CINAHL were searched from inception to December 19, 2022. STUDY ELIGIBILITY CRITERIA: Studies were only included if the following criteria were met: case-control or cohort studies that were conducted with human participants, were available in English, and that measured the exposure of a history of hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, chronic hypertension, or superimposed preeclampsia) and the outcome of maternal ischemic stroke or hemorrhagic stroke. METHODS: Three reviewers extracted the data and appraised the study quality following the Meta-analyses of Observational Studies in Epidemiology guidelines and using the Newcastle-Ottawa scale for risk of bias assessment. RESULTS: The primary outcome was any stroke (undifferentiated) and secondary outcomes included ischemic stroke and hemorrhagic stroke. The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews under identifier CRD42021254660. Of 24 studies included (10,632,808 study participants), 8 studies examined more than 1 outcome of interest. Hypertensive disorders of pregnancy were significantly associated with any stroke (adjusted risk ratio, 1.74; 95% confidence interval, 1.45-2.10). Preeclampsia was significantly associated with any stroke (adjusted risk ratio, 1.75; 95% confidence interval, 1.56-1.97), ischemic stroke (adjusted risk ratio, 1.74; 95% confidence interval, 1.46-2.06), and hemorrhagic stroke (adjusted risk ratio, 2.77; 95% confidence interval, 2.04-3.75). Gestational hypertension was significantly associated with any stroke (adjusted risk ratio, 1.23; 95% confidence interval, 1.20-1.26), ischemic stroke (adjusted risk ratio, 1.35; 95% confidence interval, 1.19-1.53), and hemorrhagic stroke (adjusted risk ratio, 2.66; 95% confidence interval, 1.02-6.98). Chronic hypertension was associated with ischemic stroke (adjusted risk ratio, 1.49; 95% confidence interval, 1.01-2.19). CONCLUSION: In this meta-analysis, exposure to hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, seems to be associated with an increased risk for any stroke and ischemic stroke among parous patients in later life. Preventive interventions may be warranted for patients who experience hypertensive disorders of pregnancy to reduce their long-term risk for stroke.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

AIMS: To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS: Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION: These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

Heterogenous Differences in Cellular Senescent Phenotypes in Pre-Eclampsia and IUGR following Quantitative Assessment of Multiple Biomarkers of Senescence.

Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE; n = 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile; n = 6), and age-matched controls (n = 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 (p < 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident (p < 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls (p = 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102; p = 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8; p = 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication.

A proteomic profile of the healthy human placenta.

BACKGROUND: The placenta remains one of the least studied organs within the human body. Yet, placental dysfunction has been associated with various pregnancy complications leading to both maternal and fetal death and long-term health consequences. The aim of this study was to characterise the protein networks of healthy term placental sub-anatomical regions using label free quantification mass spectrometry. METHODS: Three healthy placentae were sampled at five sample sites and each biopsy was dissected into maternal-, middle-, and fetal- sub-anatomical regions. Quadrupole-orbitrap mass spectrometer was used in data dependant analysis mode to identify 1859 unique proteins before detailed differential expression between regions. RESULTS: Protein profiling identified 1081, 1086, and 1101 proteins in maternal, middle, and fetal sub-anatomical regions respectively. Differentially expressed proteins were identified considering the effect between sample site location and sub-anatomical region on protein expression. Of these, 374 differentially expressed proteins (Two-way ANOVA adjusted p-value < 0.05, HSD Tukey adjusted p-value 0.05) were identified between sample site locations and sub-anatomical regions. The placenta specific disease map NaviCenta ( https://www.sbi.uni-rostock.de/minerva/index.xhtml?id=NaviCenta ) was used to focus functional analysis results to the placenta specific context. Subsequently, functional analysis with a focus on senescence, and mitochondrial function were performed. Significant differences were observed between sub-anatomical regions in protein intensity and composition. A decrease in anti-senescent proteins within the maternal sub-anatomical region, and an increase in proteins associated with a switch from ATP to fatty acid consumption as a source of energy between middle and fetal sub-anatomical regions were observed. CONCLUSION: These results suggest that normal proteomic variations exist within the anatomical structure of the placenta, thus recommending serial sectioning methodology for consistent placental research.

Maternal and perinatal outcomes following a diagnosis of Hodgkin lymphoma during or prior to pregnancy: A systematic review.

BACKGROUND: The initial peak incidence of Hodgkin lymphoma (HL) occurs during reproductive years. OBJECTIVES: Synthesise published literature on the relationship between HL and maternal and perinatal outcomes. SEARCH STRATEGY: Systematic search of PubMed/Medline, Cochrane Library, Scopus, Embase and Science Direct from inception to June 2022, supplemented by hand-searching reference lists. SELECTION CRITERIA: Two reviewers independently reviewed titles, abstracts and full-text articles. Published studies containing original data were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and appraised study quality. Outcomes for pregnant women with a previous/current diagnosis of HL were compared separately with women never diagnosed with HL. Where data permitted, meta-analyses of odds ratios and proportions were performed. Certainty of evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. MAIN RESULTS: Of the 5527 studies identified, 33 met the inclusion criteria. In the groups with HL before pregnancy and HL during pregnancy, adjusted odds ratios were not statistically significant for congenital malformation (aOR 1.7, 95% CI 0.9-3.1, and aOR 1.84, 95% CI 0.81-4.15, respectively), preterm birth (PTB) (aOR 0.99, 95% CI 0.65-1.51, and aOR 6.74, 95% CI 0.52-88.03, respectively) and miscarriage (aOR 0.78, 95% CI 0.55-1.10, and aOR 0.38, 95% CI 0.05-2.72, respectively). The aORs for all other outcomes were not statistically significant, except for blood transfusion (aOR 1.38, 95% CI 1.05-1.82) and venous thromboembolism (VTE) (aOR 7.93, 95% CI 2.97-21.22) in the group for HL during pregnancy. The proportion of anaemia was also increased in this group (69%, 95% CI 57%-80% vs 4%, 95% CI 4%-5%, respectively). The GRADE certainty of findings ranged from low to very low. CONCLUSIONS: Rates of most adverse pregnancy outcomes among women with a previous/current HL diagnosis are not increased significantly compared with the general pregnant population. Women with HL diagnosed during pregnancy may have a higher PTB rate and increased likelihood of VTE, anaemia and blood transfusion; however, small study numbers and the low to very low GRADE certainty of findings preclude firm conclusions.

Association between intrapartum fetal pulse oximetry and adverse perinatal and long-term outcomes: a systematic review and meta-analysis protocol.

Background: Current methods of intrapartum fetal monitoring based on heart rate, increase the rates of operative delivery but do not prevent or accurately detect fetal hypoxic brain injury. There is a need for more accurate methods of intrapartum fetal surveillance that will decrease the incidence of adverse perinatal and long-term neurodevelopmental outcomes while maintaining the lowest possible rate of obstetric intervention. Fetal pulse oximetry (FPO) is a technology that may contribute to improved intrapartum fetal wellbeing evaluation by providing a non-invasive measurement of fetal oxygenation status. Objective: This systematic review and meta-analysis aims to synthesise the evidence examining the association between intrapartum fetal oxygen saturation levels and adverse perinatal and long-term outcomes in the offspring. Methods: We will include randomised control trials (RCTs), cohort, cross-sectional and case-control studies which examine the use of FPO during labour as a means of measuring intrapartum fetal oxygen saturation and assess its effectiveness at detecting adverse perinatal and long-term outcomes compared to existing intrapartum surveillance methods. A detailed systematic search of PubMed, EMBASE, CINAHL, The Cochrane Library, Web of Science, ClinicalTrials.Gov and WHO ICTRP will be conducted following a detailed search strategy until February 2024. Three authors will independently review titles, abstracts and full text of articles. Two reviewers will independently extract data using a pre-defined data extraction form and assess the quality of included studies using the Risk of Bias tool for RCTs and Newcastle-Ottawa Scale for observational studies. The grading of recommendations, assessment, development, and evaluation (GRADE) approach will be used to evaluate the certainty of the evidence. We will use random-effects meta-analysis for each exposure-outcome association to calculate pooled estimates using the generic variance method. This systematic review will follow the Preferred Reporting Items for Systematic reviews and Meta-analyses and MOOSE guidelines. PROSPERO registration: CRD42023457368 (04/09/2023).

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

BACKGROUND: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. METHODS: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. CONCLUSION: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. LIMITATIONS: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. FUTURE WORK: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. TRIAL REGISTRATION: The trial was prospectively registered as ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Predicting Low Cognitive Ability at Age 5-Feature Selection Using Machine Learning Methods and Birth Cohort Data.

Objectives: In this study, we applied the random forest (RF) algorithm to birth-cohort data to train a model to predict low cognitive ability at 5 years of age and to identify the important predictive features. Methods: Data was from 1,070 participants in the Irish population-based BASELINE cohort. A RF model was trained to predict an intelligence quotient (IQ) score ≤90 at age 5 years using maternal, infant, and sociodemographic features. Feature importance was examined and internal validation performed using 10-fold cross validation repeated 5 times. Results The five most important predictive features were the total years of maternal schooling, infant Apgar score at 1 min, socioeconomic index, maternal BMI, and alcohol consumption in the first trimester. On internal validation a parsimonious RF model based on 11 features showed excellent predictive ability, correctly classifying 95% of participants. This provides a foundation suitable for external validation in an unseen cohort. Conclusion: Machine learning approaches to large existing datasets can provide accurate feature selection to improve risk prediction. Further validation of this model is required in cohorts representative of the general population.

Patient-reported outcome measures evaluating postpartum maternal health and well-being: a systematic review and evaluation of measurement properties.

OBJECTIVE: This study aimed to systematically review and evaluate postpartum health and well-being using patient-reported outcome measures across all domains of postpartum health using the COnsensus-based Standards for the selection of health Measurement INstruments guidelines. DATA SOURCES: Based on a preprepared published protocol, a systematic search of PubMed, Embase, and CINAHL was undertaken to identify patient-reported outcome tools. The protocol was registered with the International Prospective Register of Systematic Reviews (registration number CRD42021283472), and this work followed the COnsensus-based Standards for the selection of health Measurement INstruments guidelines for systematic reviews. STUDY ELIGIBILITY CRITERIA: Studies eligible for inclusion included those that assessed a patient-reported outcome measure examining postpartum women's health and well-being with no limitation on the domain. The included studies aimed to evaluate one or more measurement properties of the patient-reported outcome measure. METHODS: Data extraction and the methodological assessment of the quality of the patient-reported outcome measure were assessed by 2 reviewers independently based on content validity, structural validity, internal consistency, cross-cultural validity or measurement invariance, reliability, measurement error, hypotheses testing for construct validity, and responsiveness, as defined by the COnsensus-based Standards for the selection of health Measurement INstruments. The standard used for content validity were the domains of importance to women in postpartum health and well-being proposed by the International Consortium for Health Outcomes Measurement. The outcome domains for patient-reported health status include mental health, health-related quality of life, incontinence, pain with intercourse, breastfeeding, and motherhood role transition. The quality of the methods was rated an overall rating of results, awarded a level of evidence, and assessed using the Grading of Recommendations, Assessment, Development, and Evaluations assessment tool, and a level of recommendation was awarded for each tool. RESULTS: There were 10,324 studies identified in the initial search, of which 29 tools were identified from 41 eligible studies included in the review. Moreover, 21 tools were awarded an "A" grading of recommendation for use as a patient-reported outcome measure in postpartum women following the COnsensus-based Standards for the selection of health Measurement Instruments standards. Of the "A"-rated tools, 17 (80%) examined the domain of mental health, 5 examined health-related quality of life, 4 examined breastfeeding, and 6 represented role transition. No "A"-recommended tool examined postpartum incontinence or pain with intercourse. Of note, 3 tools did not cover domains as recommended by the International Consortium for Health Outcomes Measurement, and 5 tools were awarded a "B" rating, requiring more research before their recommendation for use. Here, most tools were awarded very low-moderate Recommendations, Assessment, Development, and Evaluations level of evidence. Moreover, the highest quality tool identified that covered multiple domains of postpartum health and well-being was the women's Postpartum Quality-of-Life Questionnaire. CONCLUSION: This systematic review identified the best performing patient-reported outcome measures to assess postpartum health and well-being. No individual tool covers all 6 domains of postpartum health and well-being. Here, the highest quality tool found that covered multiple domains of postpartum health and well-being was the Postpartum Quality-of-Life Questionnaire. The Postpartum Quality-of-Life Questionnaire captures 4 of 6 domains of importance to women, with domains of incontinence and sexual health unevaluated. The domain of urinary incontinence was represented by the International Consultation on Incontinence Questionnaire Short Form, which requires further psychometric analysis before its recommended use. Postpartum sexual health, not represented by any tool, necessitates the development of a patient-reported outcome measure. A postpartum patient-reported outcome measure would be best provided by a combination of tools; however, further research is required before its implementation.