Roles of ß-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

ß-Adrenoceptors (ß-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three ß-ARs, ß1-AR, ß2-AR, ß3-AR are localized to the human heart. Activation of ß1-AR and ß2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of ß1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of ß1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of ß2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of ß2-AR in cardiovascular disease, particularly arrhythmia generation. All ß-blockers used therapeutically to treat cardiovascular disease block ß1-AR with variable blockade of ß2-AR depending on relative affinity for ß1-AR vs ß2-AR. Since the introduction of ß-blockers into clinical practice in 1965, ß-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. ß-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. ß-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The ß-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other ß-blockers and is used successfully in the treatment of heart failure. The discovery of ß3-AR in human heart created interest in the role of ß3-AR in heart failure but has not resulted in therapeutics at this stage.

Risks associated with antidepressants in patients with hypertension during pregnancy: a retrospective cohort study.

PURPOSE: In a cohort of pregnant women using antihypertensive drugs, we compared exposure to antidepressants versus no exposure and the possible association with birth weight, APGAR scores, NICU admission, and maternal admission to an obstetrical intensive care unit (OHC). It was hypothesized that pregnant women with hypertensive disorders using antidepressants are at greater risk of complications. METHODS: A retrospective cohort study in a general teaching hospital in Zwolle, in the Middle-Northern part of The Netherlands. Finally, 58 pregnancies in the exposed group and 273 pregnancies in the reference group met all inclusion and exclusion criteria. We compared the neonate's birthweight between the exposed to antidepressants group and the reference group as the primary outcome. Secondary outcomes were the APGAR score at 1 and 5 min and obstetric high care (OHC) admission of the mother and neonatal intensive care unit (NICU) admission of the child. RESULTS: We found no differences in birth weight in neonates of mothers with hypertensive disorders and whether or not to use antidepressants. Besides a possible higher risk of admission to an OHC in women with hypertension-complicated pregnancies using antidepressants, we found no other maternal or neonatal risks in this population. CONCLUSION: We found no additional maternal or neonatal risks of using antidepressants prescribed to women with hypertension disorders during pregnancy.

Who Needs a Second Dose of Exogenous Surfactant?

OBJECTIVE: To identify prenatal and postnatal risk factors associated with surfactant redosing. STUDY DESIGN: Retrospective, single-regional center study including all infants born from 24 + 0 to 31 + 6 weeks of gestation in the Marche Region, Italy, and admitted to a single level III regional NICU from January 1, 2004, to February 28, 2021. Clinical factors associated with surfactant redosing were identified through logistic regression analysis. RESULTS: Of 1615 consecutive admissions, 662 infants were treated with exogenous surfactant: 462 (70%) received a single dose and 200 (30%) received more than 1 dose (25.5% two doses and 4.5% three doses). Risk of redosing was higher for infants born to mothers with hypertension in pregnancy (OR 3.95, P < .001), for small for gestational age (SGA) infants (OR 3.93, P < .001) and when the first surfactant dose was 100 mg/kg instead of 200 mg/kg (OR 4.56/4.61, P < .001). Infants with greater GA, delayed first surfactant administration, and milder respiratory distress syndrome had reduced risk of redosing. Infants who required multiple surfactant doses had a higher rate of bronchopulmonary dysplasia and mortality, as well as longer duration of respiratory support than patients that received 1 dose. CONCLUSIONS: Hypertension in pregnancy and SGA status were found to be statistically and clinically significant predictors of surfactant redosing. Understanding the pathophysiology of these conditions requires further investigation.

American College of Cardiology and American Heart Association blood pressure categories-a systematic review of the relationship with adverse pregnancy outcomes in the first half of pregnancy.

OBJECTIVE: A relationship between the 2017 American College of Cardiology and American Heart Association blood pressure thresholds and adverse pregnancy outcomes has been reported, but few studies have explored the diagnostic test properties of these cutoffs. DATA SOURCES: We systematically searched electronic databases (from 2017 to 2021) for reports of blood pressure measurements in pregnancy, classified according to 2017 American College of Cardiology and American Heart Association criteria, and their relationship with pregnancy outcomes. STUDY ELIGIBILITY CRITERIA: Studies recording blood pressure at <20 weeks gestation were included. METHODS: Meta-analyses were used to investigate the strength of the association between blood pressure cutoffs and adverse outcomes, and the diagnostic test properties were calculated. RESULTS: Of 23 studies included, there was a stepwise relationship between the American College of Cardiology and American Heart Association blood pressure category (when compared with normal blood pressure of <120/80 mmHg) and the strength of the association with preeclampsia. The category of elevated blood pressure had a risk ratio of 2.0 (95% prediction interval, 0.8-4.8), the stage 1 hypertension category had a risk ratio of 3.0 (95% prediction interval, 1.1-8.5), and the stage 2 hypertension category had a risk ratio of 7.9 (95% prediction interval, 1.8-35.1). Between-study variability was related to the magnitude of the association with stronger relationships in larger studies at low risk of bias and with unselected populations with multiple routine blood pressure measurements. None of the systolic blood pressure measurements of <120 mmHg, <130/80 mmHg, or <140/90 mmHg were useful to rule out the development of preeclampsia (all negative likelihood ratios >0.2). Only a blood pressure measurement of ≥140/90 mmHg was a good predictor for the development of preeclampsia (positive likelihood ratio, 5.95). The findings were similar for other outcomes. CONCLUSION: Although a blood pressure of 120 to 140 over 80 to 90 mmHg at <20 weeks gestation is associated with a heightened risk for preeclampsia and adverse pregnancy outcomes and may assist in risk prediction in multivariable modelling, lowering the diagnostic threshold for chronic hypertension would not assist clinicians in identifying women at heightened risk.

Metabolic profiling of pregnancies complicated by preeclampsia: A longitudinal study.

INTRODUCTION: Preeclampsia is associated with maternal metabolic disturbances, but longitudinal studies with comprehensive metabolic profiling are lacking. We aimed to determine metabolic profiles across gestation in women who developed preeclampsia compared with women with healthy pregnancies. We also explored the respective effects of body mass index (BMI) and preeclampsia on various metabolic measures. MATERIAL AND METHODS: We measured 91 metabolites by high-throughput nuclear magnetic resonance spectroscopy at four time points (visits) during pregnancy (weeks 14-16, 22-24, 30-32 and 36-38). Samples were taken from a Norwegian pregnancy cohort. We fitted a linear regression model for each metabolic measure to compare women who developed preeclampsia (n = 38) and healthy controls (n = 70). RESULTS: Among women who developed preeclampsia, 92% gave birth after 34 weeks of gestation. Compared to women with healthy pregnancies, women who developed preeclampsia had higher levels of several lipid-related metabolites at visit 1, whereas fewer differences were observed at visit 2. At visit 3, the pattern from visit 1 reappeared. At visit 4 the differences were larger in most subgroups of very-low-density lipoprotein particles, the smallest high-density lipoprotein, total lipids and triglycerides. Total fatty acids were also increased, of which monounsaturated fatty acids and saturated fatty acids showed more pronounced differences. Concentration of glycine tended to be lower in pregnancies with preeclampsia until visit 3, although this was not significant after correction for multiple testing. After adjustment for age, BMI, parity and gestational weight gain, all significant differences were attenuated at visits 1 and 2. The estimates were less affected by adjustment at visits 3 and 4. CONCLUSIONS: In early pregnancy, the metabolic differences between preeclamptic and healthy pregnancies were primarily driven by maternal BMI, probably representing the women's pre-pregnancy metabolic status. In early third trimester, several weeks before clinical manifestation, the differences were less influenced by BMI, indicating preeclampsia-specific changes. Near term, women with preeclampsia developed an atherogenic metabolic profile, including elevated total lipids, very-low-density lipoprotein, triglycerides, and total fatty acids.

Risk factors associated with attendance at postpartum blood pressure follow-up visit in discharged patients with hypertensive disorders of pregnancy.

BACKGROUND: This study aims to investigate the risk factors for not returning to postpartum blood pressure (BP) follow-up visit at different time points in postpartum discharged hypertensive disorders of pregnancy (HDP) patients. Likewise, females with HDP in China should have a BP evaluation continuously for at least 42 days postpartum and have BP, urine routine, and lipid and glucose screening for 3 months postpartum. METHODS: This study is a prospective cohort study of postpartum discharged HDP patients. Telephone follow-up was conducted at 6 weeks and 12 weeks postpartum, the maternal demographic characteristics, details of labor and delivery, laboratory test results of patients at admission, and adherence to BP follow-up visits postpartum were collected. While logistic regression analysis was used to analyze the factors associated with not returning to postpartum BP follow-up visit at 6 weeks and 12 weeks after delivery, the receiver operating characteristic (ROC) curve was drawn to evaluate the model's predictive value for predicting not returning to postpartum BP visit at each follow-up time point. RESULTS: In this study, 272 females met the inclusion criteria. 66 (24.26%) and 137 (50.37%) patients did not return for postpartum BP visit at 6 and 12 weeks after delivery. A multivariate logistic regression analysis identified education level of high school or below (OR = 3.71; 95% CI = 2.01-6.85; p = 0.000), maximum diastolic BP during pregnancy (OR = 0.97; 95% CI = 0.94-0.99; p = 0.0230)and delivery gestational age (OR = 1.12; 95% CI = 1.005-1.244; p = 0.040)as independent risk factors in predicting not returning to postpartum BP follow-up visit at 6 weeks postpartum, and education level of high school or below (OR = 3.20; 95% CI = 1.805-5.67; p = 0.000), maximum diastolic BP during pregnancy (OR = 0.95; 95% CI = 0.92-0.97; p = 0.000), delivery gestational age (OR = 1.13; 95% CI = 1.04-1.24; p = 0.006) and parity (OR = 1.63; 95% CI = 1.06-2.51; p = 0.026) as risk factors for not returning to postpartum BP follow-up visit at 12 weeks postpartum. The ROC curve analysis indicated that the logistic regression models had a significant predictive value for identify not returning to BP follow-up visit at 6 and 12 weeks postpartum with the area under the curve (AUC) 0.746 and 0.761, respectively. CONCLUSION: Attendance at postpartum BP follow-up visit declined with time for postpartum HDP patients after discharge. Education at or below high school, maximum diastolic BP during pregnancy and gestational age at delivery were the common risk factors for not returning for BP follow-up visit at 6 and 12 weeks postpartum in postpartum HDP patients.

Provision and experience of care among women with hypertension in pregnancy: a multi-center qualitative study in Ghana.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) remain a leading global health problem with complex clinical presentations and potentially grim birth outcomes for both mother and fetus. Improvement in the quality of maternal care provision and positive women's experiences are indispensable measures to reduce maternal and perinatal adverse outcomes. OBJECTIVE: To explore the perspectives and lived experiences of healthcare provision among women with HDP and the associated challenges. METHODS: A multi-center qualitative study using in-depth interviews (IDIs) and focus group discussions (FGDs) was conducted in five major referral hospitals in the Greater Accra Region of Ghana between June 2018 and March 2019. Women between 26 and 34 weeks' gestation with confirmed HDP who received maternity care services were eligible to participate. Thematic content analysis was performed using the inductive analytic framework approach. RESULTS: Fifty IDIs and three FGDs (with 22 participants) were conducted. Most women were between 20 and 30 years, Akans (ethnicity), married/cohabiting, self-employed and secondary school graduates. Women reported mixed (positive and negative) experiences of maternal care. Positive experiences reported include receiving optimal quality of care, satisfaction with care and good counselling and reassurance from the health professionals. Negative experiences of care comprised ineffective provider-client communication, inappropriate attitudes by the health professionals and disrespectful treatment including verbal and physical abuse. Major health system factors influencing women's experiences of care included lack of logistics, substandard professionalism, inefficient national health insurance system and unexplained delays at health facilities. Patient-related factors that influenced provision of care enumerated were financial limitations, chronic psychosocial stress and inadequate awareness about HDP. CONCLUSION: Women with HDP reported both positive and negative experiences of care stemming from the healthcare system, health providers and individual factors. Given the importance of positive women's experiences and respectful maternal care, dedicated multidisciplinary women-centered care is recommended to optimize the care for pregnant women with HDP.

High blood pressure (hypertension) in pregnancy can have severe complications for both mother and fetus including loss of life. The outcome of pregnancy for women who develop hypertension during pregnancy can be improved by ensuring optimal quality of care. In this study, we explored the opinions and experiences of women whose pregnancies were affected by hypertension concerning the care they received during their recent admission at different hospitals in Ghana and the challenges they faced. In four major referral hospitals in the Greater Accra Region of Ghana, we interviewed the women and had focus group discussions. Women who were pregnant for 26 weeks up to 34 weeks and had hypertension in pregnancy were invited for inclusion in the study.We conducted in-depth interviews with fifty women and three focus group discussions with 22 women. Most women who participated in the study were between 20 and 30 years old, Akans (ethnicity), married/cohabiting, self-employed and secondary school graduates. The women reported both positive and negative experiences of care during their admission at the hospitals. Examples of positive experiences were receiving good quality of care, satisfaction with care, and adequate counselling from the health workers. Examples of negative experiences were poor communication between the providers and affected women, inappropriate attitudes by the healthcare providers, and disrespectful treatment such as verbal and physical abuse. The major factors in the health system that influenced women's experiences of care were lack of logistics, substandard professionalism, inefficient national health insurance system and long delays at health facilities prior to receiving treatment. The individual women's factors that affected the quality of care included financial constraints, psychosocial stress and inadequate knowledge about hypertension during pregnancy.In conclusion, we determined that women with hypertension in pregnancy experience both positive and negative aspects of care and these may be due to challenges associated with the healthcare system, health providers and women themselves. There is the need to ensure optimal quality and respectful maternity care considering the nature of hypertension in pregnancy. These women require dedicated hospital staff with significant  experience to improve the quality of care provided to women with hypertension in pregnancy.

Alterations in Antioxidant Micronutrient Concentrations in Placental Tissue, Maternal Blood and Urine and the Fetal Circulation in Pre-eclampsia.

Trace elements such as selenium and zinc are vital components of many enzymes, including endogenous antioxidants, and can interact with each other. Women with pre-eclampsia, the hypertensive disease of pregnancy, have been reported as having changes in some individual antioxidant trace elements during pregnancy, which are related to maternal and fetal mortality and morbidity. We hypothesised that examination of the three compartments of (a) maternal plasma and urine, (b) placental tissue and (c) fetal plasma in normotensive and hypertensive pregnant women would allow identification of biologically significant changes and interactions in selenium, zinc, manganese and copper. Furthermore, these would be related to changes in the angiogenic markers, placental growth factor (PlGF) and Soluble Fms-Like Tyrosine Kinase-1 (sFlt-1) concentrations. Venous plasma and urine were collected from healthy non-pregnant women (n = 30), normotensive pregnant controls (n = 60) and women with pre-eclampsia (n = 50) in the third trimester. Where possible, matched placental tissue samples and umbilical venous (fetal) plasma were also collected. Antioxidant micronutrient concentrations were measured by inductively coupled plasma mass-spectrometry. Urinary levels were normalised to creatinine concentration. Plasma active PlGF and sFlt-1 concentrations were measured by ELISA. Maternal plasma selenium, zinc and manganese were all lower in women with pre-eclampsia (p < 0.05), as were fetal plasma selenium and manganese (p < 0.05 for all); maternal urinary concentrations were lower for selenium and zinc (p < 0.05). Conversely, maternal and fetal plasma and urinary copper concentrations were higher in women with pre-eclampsia (p < 0.05). Differences in placental concentrations varied, with lower overall levels of selenium and zinc (p < 0.05) in women with pre-eclampsia. Maternal and fetal PlGF were lower and sFlt-1 higher in women with pre-eclampsia; maternal plasma zinc was positively correlated with maternal plasma sFlt-1 (p < 0.05). Because of perceptions that early- and late-onset pre-eclampsia have differing aetiologies, we subdivided maternal and fetal data accordingly. No major differences were observed, but fetal sample sizes were small following early-onset. Disruption in these antioxidant micronutrients may be responsible for some of the manifestations of pre-eclampsia, including contributing to an antiangiogenic state. The potential benefits of mineral supplementation, in women with deficient intakes, during pregnancy to reduce pre-eclampsia remain an important area for experimental and clinical research.

Racial Disparities in Diagnosis, Management, and Outcomes in Preeclampsia.

PURPOSE OF THE REVIEW: Racial disparities are prevalent in many aspects of obstetric care in the USA. Non-Hispanic black women have a higher prevalence of the diagnosis of hypertensive disorders of pregnancy in addition to associated morbidity and mortality. The purpose of this review is to review current data regarding racial disparities in the diagnosis and management of hypertensive disorders of pregnancy. RECENT FINDINGS: Diagnosis of hypertensive disorders of pregnancy is more common among non-Hispanic black women even after adjustment for comorbidities. Furthermore, prevalence of severe morbidity among those with hypertensive disorders of pregnancy is increased in non-Hispanic black women, including cardiovascular events related. Proposed management solutions include quality improvement initiatives, telehealth, and strategies to reduce both structural racism and implicit bias. Racial disparities exist in both diagnosis and management of hypertensive disorders of pregnancy; further innovative work is needed to reduce these disparities.

Ophthalmic artery peak systolic velocity ratio distinguishes pre-eclampsia from chronic and gestational hypertension: A prospective cohort study.

OBJECTIVE: To examine whether the ophthalmic artery peak systolic velocity ratio (OA PSV-ratio) is higher in women with pre-eclampsia compared with gestational hypertension (GH) and chronic hypertension (CH), after controlling for confounding variables. DESIGN: Prospective cohort. SETTING: Specialist hypertension clinic in a tertiary referral centre. POPULATION: Singleton pregnancies presenting between 32+0 and 36+6  weeks of gestation with pre-eclampsia (n = 50), GH (n = 54) and CH (n = 56). METHODS: Paired measurements of maternal mean arterial pressure (MAP) and OA PSV-ratio were performed by trained sonographers. Multiple linear regression was fitted to the OA PSV-ratio, including maternal characteristics and medical history, GH, pre-eclampsia and MAP and use of antihypertensive medication. MAIN OUTCOME MEASURE: Whether pre-eclampsia is independently associated with higher OA PSV-ratio. RESULTS: MAP was significantly higher in both GH (p = 0.0015) and pre-eclampsia (p = 0.008) than in CH pregnancies. There was no significant difference between pre-eclampsia and GH (0.670). The OA PSV-ratio was significantly higher in pre-eclampsia than CH (p = 0.0008) and GH (p = 0.015). There was no significant difference between the OA PSV-ratio in CH and GH (p = 0.352). Multiple linear regression modelling showed that the OA PSV-ratio was influenced by maternal weight (p = 0.005), maternal age (p = 0.014), antihypertensive medications (p = 0.007) and MAP (p < 0.0001). After controlling for these variables, the OA PSV-ratio was still significantly higher in those with pre-eclampsia (p = 0.0002). CONCLUSIONS: The OA PSV-ratio is influenced by maternal weight, age, antihypertensive medications and MAP. Pre-eclampsia is an independent predictor of OA PSV-ratio, which therefore may be a useful point-of-care test when assessing women presenting with hypertension.

Changes in ophthalmic artery Doppler during acute blood-pressure control in hypertensive pregnant women.

OBJECTIVE: To examine the changes in ophthalmic artery Doppler indices and their association with changes in mean arterial blood pressure (MAP) and systolic (SBP) and diastolic (DBP) blood pressure, following acute antihypertensive treatment in women with hypertensive disorders of pregnancy presenting with high blood pressure. METHODS: This was a prospective cohort study of 31 pregnant women presenting at 30 + 0 to 39 + 6 weeks' gestation for management of their hypertension. Paired maternal blood-pressure and ophthalmic-artery-Doppler measurements were performed prior to and at 30 min and 60 min after starting antihypertensive medication. In patients who did not achieve blood-pressure control (i.e. when blood pressure was < 140/90 mmHg) by 60 min, paired readings were continued up to 120 min. If blood-pressure control was still not achieved at that point, patients were admitted to hospital. Univariate linear regression was performed to determine the association of ophthalmic artery peak systolic velocity (PSV) ratio with SBP, DBP and MAP before treatment and after blood-pressure control. The longitudinal changes in MAP, SBP, DBP and PSV ratio from pretreatment to 30 min and 60 min after commencement of antihypertensives were examined by repeated measure, multilevel, linear mixed-effects analysis. RESULTS: Antihypertensive treatment was associated with a decrease in SBP, DBP, MAP and PSV ratio. At 60 min following antihypertensive treatment, the decrease in SBP, DBP, MAP and PSV ratio was 12.1 mmHg (95% CI, 9.0-15.1 mmHg; P < 0.0001), 9.1 mmHg (95% CI, 6.5-11.5 mmHg; P < 0.0001), 10.0 mmHg (95% CI, 7.6-12.4 mmHg; P < 0.0001) and 0.07 (95% CI, 0.03-0.11 mmHg; P < 0.001), respectively. From the total cohort, 20 (64.5%) women had achieved blood-pressure control at 60 min and another seven (22.6%) by 120 min from commencement of antihypertensive treatment. Four (12.9%) women did not achieve blood-pressure control during this period and were admitted to hospital. The relationship between PSV ratio and SBP, DBP and MAP was assessed before treatment (n = 31) and at the point of blood-pressure control in women in whom this was achieved by 120 min (n = 27). Prior to treatment, there was a significant association between PSV ratio and MAP (P < 0.0001, R2 = 0.39). This was primarily due to the association of PSV ratio with DBP (P < 0.0001, R2 = 0.39) and less so due to its association with SBP (P = 0.02, R2 = 0.16). At the point of achieving blood-pressure control, there was no significant association between PSV ratio and MAP (P = 0.7), DBP (P = 0.5) or SBP (P = 0.7). CONCLUSIONS: Acute blood-pressure control in pregnancy is associated with a concomitant reduction in blood pressure and ophthalmic artery PSV ratio. In hypertensive pregnant women, there is a significant association of PSV ratio with MAP, SBP and DBP, which disappears after blood pressure is reduced to < 140/90 mmHg following antihypertensive treatment. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Hypertensive disorders of pregnancy and breastfeeding practices: A secondary analysis of data from the All Our Families Cohort.

INTRODUCTION: Hypertensive disorders of pregnancy occur in approximately 7%-10% of pregnancies and are associated with adverse maternal cardiovascular health outcomes across the lifespan. In contrast, breastfeeding has been associated with a reduction in cardiovascular risk factors in a dose-dependent manner. Despite the potential protective effects of lactation on cardiovascular risk, how hypertensive disorders of pregnancy relate to breastfeeding practices and experiences is not well understood. The aim of this study was to investigate the association between hypertensive disorders of pregnancy and breastfeeding outcomes in the first year postpartum. MATERIAL AND METHODS: We conducted a secondary analysis of prospective data from the All Our Families Cohort, a population-based study conducted in Calgary, Alberta, Canada. Women with a singleton pregnancy (n = 1418) who completed self-report questionnaires at <25 weeks and 34-36 weeks of gestation, and 4 months and 12 months postpartum, and provided consent to link to electronic medical records that identified diagnoses of hypertensive disorders of pregnancy (n = 122). Logistic and multiple linear regression analyses were used to model associations between hypertensive disorders of pregnancy and breastfeeding outcomes. Outcomes included breastfeeding intention, intended duration, exclusive breastfeeding at 4 months, breastfeeding duration at 12 months and breastfeeding difficulties. RESULTS: Hypertensive disorders of pregnancy were not associated with breastfeeding intention (odds ration [OR] 1.30, 95% confidence interval [CI] 0.47-3.03, P = 0.57), intended breastfeeding duration (b = -3.28, 95% CI -7.04 to 0.48, P = 0.09), or initiation (OR = 0.64, 95% CI 0.29- 1.65, P = 0.32), but were associated with an increase in the odds of non-exclusive breastfeeding at 4 months postpartum (OR = 2.11, 95% CI 1.39-3.22, P < 0.001). Women with hypertensive disorders breastfed for 6.26 (95% CI -10.00 to -2.51, P < 0.001) weeks less over 12 months postpartum, had significantly higher odds of reporting insufficient milk supply (OR = 1.75, 95% CI 1.19-2.46, P < 0.05) and had lower odds of breast and/or nipple pain (OR = 0.66, 95% CI 0.44-0.92, P < 0.05) compared with those without hypertensive disorders of pregnancy. CONCLUSIONS: Hypertensive disorders of pregnancy are associated with altered breastfeeding practices and experiences during the first year postpartum. Further research is needed to examine biopsychosocial mechanisms through which hypertensive disorders associate with shorter breastfeeding duration, and to examine whether greater breastfeeding duration, intensity or exclusivity reduces short- or long-term maternal cardiovascular risk.

Placental findings in singleton stillbirths: a case-control study from a tertiary-care center in India.

OBJECTIVES: Placental examination in a case of stillbirth can provide insight into causative/associated factors with fetal demise. The aim of this study was to compare placental and umbilical cord pathologies in singleton stillbirth and livebirth placentas, and to find prevalence of various associated maternal and fetal clinical factors. METHODS: This case-control study was conducted at a tertiary-care center in India over a period of 20 months. About 250 women who delivered stillborn fetus ≥28 weeks' gestation and 250 maternal-age-matched controls were recruited. Sociodemographic and clinical details were noted and placental gross and microscopic examination was done. Placental findings were compared between stillbirth and livebirth (overall), preterm stillbirth and preterm livebirth as well as term stillbirth and term livebirth in six categories - placenta gross, cord gross, membranes gross, maternal vascular malperfusion, fetal vascular malperfusion and inflammatory response. Prevalence of 11 maternal and fetal factors were studied in all categories of placental findings in both livebirth and stillbirth. RESULTS: Placental findings in all six categories were significantly associated with stillbirths (p<0.05). The placental findings associated with stillbirth with highest odds included placental hypoplasia (OR 9.77, 95% CI 5.46-17.46), necrotizing chorioamnionitis (OR 9.30, 95% CI 1.17-73.96) and avascular villi (OR 8.45, 95% CI 3.53-20.25). More than half of the women with stillbirths had medical disorders (n=130, 52.0%) and the most prevalent was hypertensive disorder (n=45, 18.0%). CONCLUSIONS: Changes in placenta are associated with development of stillbirth. Therefore, antenatal investigations to identify placental dysfunction should be investigated to determine whether these reduce stillbirth. Also, placental examination in a case of stillbirth can detect/diagnose many maternal/fetal conditions and thereby can help in preventing future stillbirths.

Value of soluble fms-like tyrosine kinase-1/placental growth factor test in third trimester of pregnancy for predicting preeclampsia in asymptomatic women.

OBJECTIVES: To estimate the value of screening maternal serum soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio in asymptomatic women during 3rd trimester to predict preeclampsia (PE) development. METHODS: The investigated group comprised of 178 pregnant women. During this gestation, 24 cases had developed PE and 12 isolated gestational hypertension (GH); whereas 142 remained normotensive. Blood samples were collected between 180 and 259 gestational days (g.d.) when the participants were asymptomatic. Serums were analyzed using the BRAHMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio test (Thermo Fisher Scientific, Henningdorf, Germany). High-risk pregnancies for the PE development were defined as sFlt-1/PlGF>38. RESULTS: The detection rate (DR) for manifestation of PE≤30 days after sampling was 83.3% and overall DR during pregnancy 58.3%. Ten of 15 women having false positive prediction of PE suffered from GH, preterm birth and/or delivery of a small-for-gestational-age-newborn. False positive rate was significantly higher at 239-253 g.d. compared to sampling at 210-224 g.d. and 225-238 g.d. (21.9% vs. 7.8% and 5.3%; p < 0.05). CONCLUSIONS: The sFlt-1/PlGF test during 180-259 g.d. detected approximately half of subsequent PE cases. An optimal time to use the test for screening purposes was estimated 225-238 g.d. (DR 66.7%). False positive test results were more common to cases with other adverse pregnancy outcomes and samples drawn at higher gestational age.

Added prognostic value of longitudinal changes of angiogenic factors in early-onset severe pre-eclampsia: a prospective cohort study.

OBJECTIVE: To assess in women with early-onset severe pre-eclampsia whether longitudinal changes in angiogenic factors improve the prediction of adverse outcome. DESIGN: Prospective cohort study. SETTING: Maternity units in two Spanish hospitals. POPULATION: Women with diagnosis of early-onset severe pre-eclampsia. METHODS: Levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-) and sFlt-1/PlGF ratio were measured at admission and before delivery, and average daily change calculated. The association of longitudinal changes of angiogenic factors with the time interval to delivery and with complications was evaluated by logistic and Cox regression. MAIN OUTCOME MEASURES: Interval to delivery and composite of adverse outcomes. RESULTS: We included 63 women, of which 26 (41.3%) had a complication. Longitudinal changes of sFlt-1 were more pronounced in complicated pregnancies (median: 1047 versus 342 pg/ml/day; P = 0.04). On the multivariate analysis, the clinical risk score and sFlt-1 at admission explained 6.2% of the uncertainty for complication; the addition of sFlt-1 longitudinal changes improved this to 25.3% (P = 0.002). The median time from admission to delivery was 4 days (95% CI 1.6-6.04) in those in the highest quartile of sFlt-1 longitudinal changes versus 16 days (95% CI 12.4-19.6) in the remaining women (Log-rank test P < 0.001). CONCLUSIONS: Longitudinal changes in sFlt-1 maternal levels from admission for confirmed early-onset severe pre-eclampsia add to baseline characteristics in the prediction of adverse outcome and interval to delivery. TWEETABLE ABSTRACT: In early-onset severe pre-eclampsia, longitudinal changes in sFlt-1 levels improve the prediction of complications and interval to delivery.

Increased Placental Cell Senescence and Oxidative Stress in Women with Pre-Eclampsia and Normotensive Post-Term Pregnancies.

Up to 11% of pregnancies extend to post-term with adverse obstetric events linked to pregnancies over 42 weeks. Oxidative stress and senescence (cells stop growing and dividing by irreversibly arresting their cell cycle and gradually ageing) can result in diminished cell function. There are no detailed studies of placental cell senescence markers across a range of gestational ages, although increased levels have been linked to pre-eclampsia before full term. This study aimed to determine placental senescence and oxidative markers across a range of gestational ages in women with uncomplicated pregnancies and those with a diagnosis of pre-eclampsia. Placentae were obtained from 37 women with uncomplicated pregnancies of 37-42 weeks and from 13 cases of pre-eclampsia of 31+2-41+2 weeks. The expression of markers of senescence, oxidative stress, and antioxidant defence (tumour suppressor protein p16INK4a, kinase inhibitor p21, interleukin-6 (IL-6), NADPH oxidase 4 (NOX4), glutathione peroxidases 1, 3, and 4 (GPx1, GPx3, and GPx4), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)) genes was measured (quantitative real-time PCR). Protein abundance of p16INK4a, IL-6, NOX4, 8-hydroxy-2'-deoxy-guanosine (8-OHdG), and PlGF was assessed by immunocytochemistry. Placental NOX4 protein was higher in post-term than term deliveries and further increased by pre-eclampsia (p < 0.05 for all). P21 expression was higher in post-term placentae (p = 0.012) and in pre-eclampsia (p = 0.04), compared to term. Placental P16INK4a protein expression was increased post-term, compared to term (p = 0.01). In normotensive women, gestational age at delivery was negatively associated with GPx4 and PlGF (mRNA and protein) (p < 0.05 for all), whereas a positive correlation was seen with placental P21, NOX4, and P16INK4a (p < 0.05 for all) expression. Markers of placental oxidative stress and senescence appear to increase as gestational age increases, with antioxidant defences diminishing concomitantly. These observations increase our understanding of placental health and may contribute to assessment of the optimal gestational age for delivery.

An evaluation of the influence of the publication of the UK National Institute for health and Care Excellence's guidance on hypertension in pregnancy: a retrospective analysis of clinical practice.

BACKGROUND: The UK National Institute for health and Care Excellence (NICE) publish guidance aimed at standardising practice. Evidence regarding how well recommendations are implemented and what clinicians think about guidance is limited. We aimed to establish the extent to which the NICE Hypertension in pregnancy (HIP) guidance has influenced care and assess clinician's attitudes to this guidance. METHODS: Five maternity units in the Midlands and North of England took part in the retrospective evaluation of 2490 birth records from randomly selected dates in 2008-2010 and 2013-2015. The proportion of women where care was adhered to before (2008-2010) and after (2013-2015) guidance publication was examined and differences estimated. Eleven midwives and obstetricians employed by Bradford Hospitals were interviewed. RESULTS: The proportion of high risk women prescribed Aspirin rose (before 14%, after 54%, p = < 0.01 (confidence interval of change (CI) 37, 43%) as well as for moderate risk women (before 3%, after 54%, p = < 0.01, CI 48, 54%) following guidance publication. Three quarters had blood pressure and a third proteinuria measured at every antenatal visit before and after guidance. Early birth < 37 weeks and ≥ 37 weeks gestation was more frequently offered after guidance publication than before (< 37 weeks: before 9%, after 18%, p = 0.01, CI 2, 16% and ≥ 37 weeks before 30%, after 52%, p = < 0.01, CI 9, 35%). Few were informed of future risk of developing a hypertensive disorder or had a documented postnatal review; however there was an increase in women advised to see their GP for this review (58% before and 90% after guidance p = < 0.01, CI 24, 39%). All clinicians said the NICE HIP guidance was informative and provided robust evidence, however they said length of the document made use in practice challenging. They did not always access NICE guidance, preferring to use local guidance at least initially; both obstetricians and midwives said they accessed NICE guidance for in-depth information. CONCLUSIONS: NICE HIP guidance is valued, used by clinicians and has influenced important aspects of care that may help improve outcomes for women who develop hypertension or pre-eclampsia, however some recommendations have had limited impact and therefore interventions are required to improve adherence.

Wave intensity analysis of maternal arterial stiffness: augmentation index and pulse wave velocity in pregnancies complicated by diabetes or hypertension.

PURPOSE: The aim of our study was to compare the maternal arterial stiffness in pregnant women with diabetic disease, hypertension and those with normal pregnancies. METHODS: A cross-sectional study was performed involving 65 pregnant women with diabetic disease (DD group), 26 pregnant women with hypertension (RR group) and 448 women with normal pregnancies (control group). The augmentation index (AIx) and the pulse wave velocity (PWV) of the right carotid artery were assessed using non-invasive sonographic wave intensity analysis. Furthermore, the reliability of the measurements was evaluated in 21 healthy women. RESULTS: Compared with the controls, the AIx and PWV were increased in the DD group [11.0 (interquartile range, IQR 7.3, 15.2) vs. 5.7 (IQR 2.4, 9.3), P < 0.001; 5.7 (IQR 5.1, 6.4) vs. 5.2 (IQR 4.6, 6.1), P = 0.001; respectively] and the RR group [9.3 (IQR 6.6, 11.5) vs. 5.7 (IQR 2.4, 9.3), P < 0.001; 7.1 (6.3, 7.9) vs. 5.2 (IQR 4.6, 6.1), P < 0.001; respectively]. The intraclass and interclass correlation coefficients were good to excellent for the AIx (ICC: 0.91, P < 0.001 and 0.74, P < 0.002; respectively) and PWV measurements (ICC: 0.71, P < 0.004 and 0.70, P < 0.005; respectively). CONCLUSION: Pregnancies complicated by diabetic disease or hypertension are associated with increased maternal arterial stiffness. The importance of wave intensity analysis needs to be verified and larger studies are needed to establish both normal and cutoff values that may be relevant for clinical decisions.

Pre-conception management.

This communication shares two frameworks which help conceptualize the vast spectrum of pre-conception care. A 3x3 rubric classifies pre-conception assessment and interventions into gynaeco-obstetric, biomedical and psychosocial. Yet another creative checklist uses the letters A through I to present 9 aspects of pre-conception management. The aim of this article is to simplify the vast field of pre-conception care for primary care physicians and other health care professionals.

Prediction of pre-eclampsia: review of reviews.

OBJECTIVE: Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre-eclampsia, to identify high-value avenues for future research and to minimize future research waste in this field. METHODS: MEDLINE, EMBASE and The Cochrane Library including DARE (Database of Abstracts of Reviews of Effects) databases, from database inception to March 2017, and bibliographies of relevant articles were searched, without language restrictions, for systematic reviews and meta-analyses on the prediction of pre-eclampsia. The quality of the included reviews was assessed using the AMSTAR tool and a modified version of the QUIPS tool. We evaluated the comprehensiveness of search, sample size, tests and outcomes evaluated, data synthesis methods, predictive ability estimates, risk of bias related to the population studied, measurement of predictors and outcomes, study attrition and adjustment for confounding. RESULTS: From 2444 citations identified, 126 reviews were included, reporting on over 90 predictors and 52 prediction models for pre-eclampsia. Around a third (n = 37 (29.4%)) of all reviews investigated solely biochemical markers for predicting pre-eclampsia, 31 (24.6%) investigated genetic associations with pre-eclampsia, 46 (36.5%) reported on clinical characteristics, four (3.2%) evaluated only ultrasound markers and six (4.8%) studied a combination of tests; two (1.6%) additional reviews evaluated primary studies investigating any screening test for pre-eclampsia. Reviews included between two and 265 primary studies, including up to 25 356 688 women in the largest review. Only approximately half (n = 67 (53.2%)) of the reviews assessed the quality of the included studies. There was a high risk of bias in many of the included reviews, particularly in relation to population representativeness and study attrition. Over 80% (n = 106 (84.1%)) summarized the findings using meta-analysis. Thirty-two (25.4%) studies lacked a formal statement on funding. The predictors with the best test performance were body mass index (BMI) > 35 kg/m2 , with a specificity of 92% (95% CI, 89-95%) and a sensitivity of 21% (95% CI, 12-31%); BMI > 25 kg/m2 , with a specificity of 73% (95% CI, 64-83%) and a sensitivity of 47% (95% CI, 33-61%); first-trimester uterine artery pulsatility index or resistance index > 90th centile (specificity 93% (95% CI, 90-96%) and sensitivity 26% (95% CI, 23-31%)); placental growth factor (specificity 89% (95% CI, 89-89%) and sensitivity 65% (95% CI, 63-67%)); and placental protein 13 (specificity 88% (95% CI, 87-89%) and sensitivity 37% (95% CI, 33-41%)). No single marker had a test performance suitable for routine clinical use. Models combining markers showed promise, but none had undergone external validation. CONCLUSIONS: This review of reviews calls into question the need for further aggregate meta-analysis in this area given the large number of published reviews subject to the common limitations of primary predictive studies. Prospective, well-designed studies of predictive markers, preferably randomized intervention studies, and combined through individual-patient data meta-analysis are needed to develop and validate new prediction models to facilitate the prediction of pre-eclampsia and minimize further research waste in this field. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Predicción de la preeclampsia: revisión de revisiones OBJETIVO: Los estudios primarios y las revisiones sistemáticas proporcionan estimaciones de precisión variable para diferentes factores en la predicción de la preeclampsia. El objetivo de este estudio fue revisar las revisiones sistemáticas publicadas para recopilar evidencia sobre la capacidad de las pruebas disponibles para predecir la preeclampsia, identificar avenidas de investigación futura valiosas y minimizar el desperdicio futuro de investigación en este campo. MÉTODOS: Se realizaron búsquedas de artículos relevantes en bibliografías sobre el tema y en las bases de datos MEDLINE, EMBASE y The Cochrane Library, incluida DARE (Database of Abstracts of Reviews of Effects), desde el inicio de cada base de datos hasta marzo de 2017, sin restricciones de idioma, para obtener revisiones sistemáticas y metaanálisis sobre la predicción de la preeclampsia. La calidad de las revisiones incluidas se evaluó utilizando la herramienta AMSTAR y una versión modificada de la herramienta QUIPS. Se evaluó la amplitud de la búsqueda, el tamaño de la muestra, las pruebas y los resultados evaluados, los métodos de síntesis de datos, las estimaciones de la capacidad de predicción, el riesgo de sesgo relacionado con la población estudiada, la medición de los predictores y los resultados, la deserción del estudio y el ajuste por confusión. RESULTADOS: De las 2444 citas identificadas, se incluyeron 126 revisiones, que informaron sobre más de 90 predictores y 52 modelos de predicción para la preeclampsia. Alrededor de un tercio (n=37 (29,4%)) de todas las revisiones investigaron únicamente marcadores bioquímicos para predecir la preeclampsia, 31 (24,6%) investigaron asociaciones genéticas con la preeclampsia, 46 (36,5%) informaron sobre las características clínicas, cuatro (3,2%) evaluaron sólo marcadores ecográficos y seis (4,8%) estudiaron una combinación de pruebas; dos (1,6%) revisiones adicionales evaluaron los estudios primarios que investigaron cualquier prueba de diagnóstico de la preeclampsia. Las revisiones incluyeron entre dos y 265 estudios primarios, que incluyeron hasta 25 356 688 mujeres en la revisión más grande. Sólo aproximadamente la mitad (n=67 (53,2%)) de las revisiones evaluaron la calidad de los estudios incluidos. En muchas de las revisiones incluidas hubo un alto riesgo de sesgo, particularmente en relación con la representatividad de la población y la deserción de los estudios. Más del 80% (n=106 (84,1%)) resumió los hallazgos utilizando el metaanálisis. Treinta y dos (25,4%) estudios carecían de una declaración formal sobre la financiación. Los predictores con el mejor rendimiento de la prueba fueron el índice de masa corporal (IMC) >35 kg.m-2 , con una especificidad del 92% (IC 95%, 89-95%) y una sensibilidad del 21% (IC 95%, 12-31%); IMC >25 kg.m-2 , con una especificidad del 73% (IC 95%: 64-83%) y una sensibilidad del 47% (IC 95%: 33-61%); índice de pulsatilidad de la arteria uterina en el primer trimestre o índice de resistencia >90° percentil (especificidad del 93% (IC 95%: 90-96%) y sensibilidad del 26% (IC 95%: 23-31%)); factor de crecimiento placentario (especificidad 89% (IC 95%, 89-89%) y sensibilidad 65% (IC 95%, 63-67%)); y proteína placentaria 13 (especificidad 88% (IC 95%, 87-89%) y sensibilidad 37% (IC 95%, 33-41%)). Ningún marcador por sí solo tuvo un rendimiento de la prueba adecuado para el uso clínico rutinario. Los modelos que combinan marcadores son prometedores, pero ninguno fue sometido a una validación externa. CONCLUSIONES: Esta revisión de revisiones ha puesto en duda la necesidad de un metaanálisis agregado adicional en esta área, dado el gran número de revisiones publicadas sujetas a las limitaciones comunes de los estudios predictivos primarios. Se necesitan estudios prospectivos bien diseñados de marcadores predictivos, preferiblemente en estudios de intervención aleatorios, y combinados mediante el metaanálisis de datos de pacientes individuales, para desarrollar y validar nuevos modelos predictivos que faciliten la predicción de la preeclampsia y minimicen el desperdicio de investigación adicional en este campo.