The effect of VDR gene polymorphisms and vitamin D level on blood pressure,risk of preeclampsia,gestational age,and body mass index

We investigated the influence of vitamin D receptor (VDR) polymorphisms and vitamin D level on the blood pressure and the risk of preeclampsia. In a case-control study, 200 pregnant women, including 100 individuals with preeclampsia along with 100 healthy pregnant women, were studied for VDR FokI, TaqI, and BmsI polymorphisms and serum 25 (OH)-D level using polymerase chain reaction-restriction fragment length polymorphism method and commercial kit, respectively. The mean level of 25 (OH)-D in preeclamptic patients was significantly lower (16.6 ± 4.2 ng/mL, P < 0.001) compared with controls (19.6 ± 3.8 ng/mL). Among all women, a significantly higher systolic blood pressure and before-pregnancy body mass index and also lower gestational age were observed in the presence of 25 (OH)-D level < 20 ng/mL compared with the 20 to 30 ng/mL. A significantly higher frequency of VDR FokI C allele in preeclamptic patients (83%) than controls (74%) was associated with a 1.72-fold increased risk of preeclampsia. In all the studied individuals, the systolic and diastolic blood pressures were significantly higher in the presence of the FokI CC genotype compared with the TC and TT+TC genotypes. Neither VDR Taq1 nor VDR BmsI was associated with the risk of preeclampsia. The haplotype FokI C, TaqI C and BmsI A (CCA) compared with haplotype CTG increased the risk of preeclampsia by 1.4-fold (P = 0.33). Our study suggests an association between VDR FokI polymorphism and an insufficient serum level of 25 (OH)-D with the risk of preeclampsia and also the influence of insufficient 25 (OH)-D level and VDR FokI polymorphism on maternal factors, including blood pressure.     

绝经后女性血清25(OH)D水平与高血压的相关性分析

目的:探讨绝经后女性血清25羟维生素D[25(OH)D]与高血压的相关性。方法:选取456例绝经后女性为研究对象,按照是否存在高血压分为高血压组(n=102例)和非高血压组(n=354例),测定所有患者的血清25(OH)D水平;血清25(OH)D水平分为四组:即25(OH)D≥30 ng/m L组(n=50例)、21~29 ng/m L组(n=110例)、10~20 ng/m L组(n=240例)、25(OH)D10 ng/m L组(n=56例);比较各组相关指标的差异。并利用Logistic回归方程分析血清25(OH)D与高血压发生的关系。结果:高血压组与非高血压组在体质指数(BMI)、收缩压(SBP)、舒张压(SDP)、雌激素、高敏C反应蛋白(hs-CRP)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖(FPG)方面存在统计学差异(P0.05);高血压组血清25(OH)D[14.56±3.21(ng/ml)]低于非高血压组[19.89±4.75(ng/ml)](t=10.649,P0.001);在血清25(OH)D10 ng/m L组中,SBP和SDP值、高血压发生率均高于25(OH)D≥30 ng/m L组、21~29ng/m L组(n=110例)、10~20 ng/m L组(P0.05);血清25(OH)D水平与绝经后女性发生高血压呈现负相关(P0.05)。在血清25(OH)D不同分组中,从25(OH)D≥30 ng/m L组到25(OH)D10 ng/m L组发生高血压的风险值依次增加。结论:血清25(OH)D水平与绝经后高血压的发生密切相关,随着血清25(OH)D水平的逐渐降低,高血压发生的风险亦逐渐增大。     

Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk

Preeclampsia is a disorder of pregnancy diagnosed by gestational hypertension and proteinuria. Epidemiological evidence suggests that women who experience preeclampsia are at a greater risk of hypertension and heart disease later in life compared with women who had normal pregnancies. Our objective was to determine whether endothelial function is impaired in postpartum women with a history of preeclampsia in their first pregnancy. We measured forearm blood flow (FBF) by venous occlusion plethysmography in 50 healthy women: 16 with prior preeclampsia, 14 with a prior normotensive pregnancy, and 20 never pregnant controls. The postpartum women participated 6-12 mo after delivery. Heart rate (HR) and blood pressure (BP) were concurrently monitored on the contralateral arm. Hemodynamic variables were assessed at baseline and during a mental stress test known to elicit endothelium-dependent vasodilatation. We found that baseline FBF, HR, systolic BP, and diastolic BP did not significantly differ among the groups, whereas mean arterial pressure in the preeclamptic group was greater than that of the normal pregnancy group (P = 0.03). Stress-induced FBF (percent change over baseline) was reduced in the preeclamptic group compared with both the normal pregnancy and never pregnant groups (P = 0.06) and was significantly attenuated compared with women with prior normal pregnancies (91% vs. 147%, P = 0.006). These data demonstrate that women with a history of preeclampsia exhibit impaired endothelial function up to 1 yr postpartum. This observation may explain their increased risk for hypertension and cardiovascular disease.     

Single Administration of Ultra-Low-Dose Lipopolysaccharide in Rat Early Pregnancy Induces TLR4 Activation in the Placenta Contributing to Preeclampsia

Balanced immune responses are essential for the maintenance of successful pregnancy. Aberrant responses of immune system during pregnancy increase the risk of preeclampsia. Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface. This study aimed to generate a rat model of preeclampsia by lipopolysaccharide (LPS, a TLR4 agonist) administration on gestational day (GD) 5 as rats are subjected to placentation immediately after implantation between GDs 4 and 5, and to assess the contribution of TLR4 signaling to the development of preeclampsia. Single administration of 0.5 μg/kg LPS significantly increased blood pressure of pregnant rats since GD 6 (systolic blood pressure, 124.89 ± 1.79 mmHg versus 119.02 ± 1.80 mmHg, P < 0.05) and urinary protein level since GD 9 (2.02 ± 0.29 mg versus 1.11 ± 0.18 mg, P < 0.01), but barely affected blood pressure or proteinuria of virgin rats compared with those of saline-treated pregnant rats. This was accompanied with adverse pregnancy outcomes including fetal growth restriction. The expression of TLR4 and NF-κB p65 were both increased in the placenta but not the kidney from LPS-treated pregnant rats, with deficient trophoblast invasion and spiral artery remodeling. Furthermore, the levels of inflammatory cytokines were elevated systemically and locally in the placenta from pregnant rats treated with LPS. TLR4 signaling in the placenta was activated, to which that in the placenta of humans with preeclampsia changed similarly. In conclusion, LPS administration to pregnant rats in early pregnancy could elicit TLR4-mediated immune response at the maternal-fetal interface contributing to poor early placentation that may culminate in the preeclampsia-like syndrome.     

Relationship between elevated lipid peroxides,vitamin E deficiency and hypertension in preeclampsia

Preeclampsia or pregnancy-induced hypertension is a major cause of both maternal and fetal-neonatal morbidity and mortality. The deficiency of vitamin E can cause accumulation of lipid peroxidation products, which, in turn, can induce vasoconstriction. This study has examined any evidence of increased cellular lipid peroxidation and accumulation of malonydialdehyde (MDA, an end product of lipid peroxidation) in pregnancy-induced hypertension and any relationship between the elevated MDA and lower vitamin E levels with hypertension in pregnant women. EDTA-Blood was collected from pregnant women at the time of delivery. Plasma vitamin E was determined by HPLC; MDA by the thiobarbituric acid-reactivity. Subjects with diastolic blood pressure(DBP) 90 mm Hg were considered hypertensive (HT) and with <90 mm Hg normotensive (NT). Data (Mean±SE) from 49 NT and 11 HT women show that HT has significantly lower vitamin E (22±1 vs 27±1 nmole/ml, p<0.03) and elevated MDA levels (0.56±0.06 vs 0.43±0.02 nmole/ml, p<0.03) compared to NT; the ages and gestational ages of women were similar. Among all women, there was a significant positive relationship between DBP and MDA levels (r=0.27, p<0.05), and a significant negative relationship between vitamin E levels and DBP (–0.36, p<0.005), and a significant negative relationship between MDA and vitamin E levels (r=–0.27, p<0.05). Thus, HT women's plasma has significantly lower E and higher MDA levels, and DBP significantly correlates with the extent of vitamin E deficiency and increased MDA levels. This study suggests a relationship between elevated lipid peroxidation and lower vitamin E levels and hypertension in pregnancy (preeclampsia).     

血清25（OH）D、IGFBP-1、STAT4与重度子痫前期患者自发性流产的关系分析

摘要 目的：探讨血清25-羟基维生素D[25（OH）D]、胰岛素生长因子结合蛋白1（IGFBP-1）、信号转导和转录激活因子4（STAT4）与重度子痫前期（PE）患者自发性流产的关系。方法：选取2020年1月到2022年12月于徐州医科大学附属医院治疗的重度PE患者150例。根据妊娠28周内是否发生自发性流产分为发生组（n=41）和未发生组（n=109）。对比两组血清25（OH）D、IGFBP-1、STAT4水平。收集两组患者的临床资料,多因素Logistic回归分析重度PE患者自发性流产的影响因素。受试者工作特征（ROC）曲线分析血清25（OH）D、IGFBP-1、STAT4水平对重度PE患者自发性流产的预测价值。结果：发生组的25（OH）D、IGFBP-1水平低于未发生组,STAT4水平高于未发生组（P<0.05）。重度PE患者自发性流产与年龄、PE发病孕周、孕前体质量指数（BMI）、分娩史、收缩压（SBP）、舒张压（DBP）、血小板计数（PLT）、肌酐（Scr）无关（P>0.05）,而与流产史、D-二聚体（D-D）、白蛋白（ALB）、同型半胱氨酸（Hcy）、纤维蛋白原有关（P<0.05）。多因素Logistic回归分析结果显示, 25（OH）D下降、IGFBP-1下降、STAT4升高、有流产史、D-D升高、ALB下降、Hcy升高均是重度PE患者自发性流产的危险因素,而纤维蛋白原升高则是重度PE患者自发性流产的保护因素（P<0.05）。血清25（OH）D、IGFBP-1、STAT4联合检测预测自发性流产的曲线下面积（AUC）为0.960,高于单独指标预测。结论：重度PE患者血清25（OH）D、IGFBP-1下降,STAT4水平升高易导致自发性流产,自发性流产的发生还与流产史、D-D、ALB、Hcy、纤维蛋白原水平等因素有关。     

Development and Validation of a Vitamin D Status Prediction Model in Danish Pregnant Women: A Study of the Danish National Birth Cohort

Vitamin D has been hypothesized to reduce risk of pregnancy complications such as preeclampsia, gestational diabetes mellitus, and preterm delivery. However, many of these outcomes are rare and require a large sample size to study, representing a challenge for cohorts with a limited number of preserved samples. The aims of this study were to (1) identify predictors of serum 25-hydroxy-vitamin D (25(OH)D) among pregnant women in a subsample (N = 1494) of the Danish National Birth Cohort (DNBC) and (2) develop and validate a score predicting 25(OH)D-status in order to explore associations between vitamin D and maternal and offspring health outcomes in the DNBC. In our study sample, 42.3% of the population had deficient levels of vitamin D (<50 nmol/L 25(OH)D) and average levels of 25(OH)D-status were 56.7(s.d. 24.6) nmol/L. A prediction model consisting of intake of vitamin D from diet and supplements, outdoor physical activity, tanning bed use, smoking, and month of blood draw explained 40.1% of the variance in 25(OH)D and mean measured 25(OH)D-level increased linearly by decile of predicted 25(OH)D-score. In total 32.2% of the women were placed in the same quintile by both measured and predicted 25(OH)D-values and 69.9% were placed in the same or adjacent quintile by both methods. Cohen''s weighted kappa coefficient (Κ = 0.3) reflected fair agreement between measured 25(OH)D-levels and predicted 25(OH)D-score. These results are comparable to other settings in which vitamin D scores have shown similar associations with disease outcomes as measured 25(OH)D-levels. Our findings suggest that predicted 25(OH)D-scores may be a useful alternative to measured 25(OH)D for examining associations between vitamin D and disease outcomes in the DNBC cohort, but cannot substitute for measured 25(OH)D-levels for estimates of prevalence.     

Multifrequency Infradian Variation of Blood Pressure During and After Human Pregnancy

We used a chronobiologic approach to explore the possibility that there may be -7-day (circaseptan) and -30-day (circatrigintan) components in blood pressure during a healthy human pregnancy, the amenorrhea of this status notwithstanding. The results were compared with those obtained from data longitudinally monitored on the same subject at a time when she was not pregnant. The woman under study used an ABPM-630 Colin (Komaki, Japan) device to monitor her blood pressures and heart rates at half to 1-h intervals, with few interruptions. During pregnancy, starting during the first gestational week, she monitored herself for 2 of each 6-day span for the entire duration of pregnancy (a total of 76 days of monitoring). Additionally, with a monitoring protocol similar to that during pregnancy, the subject used the same blood pressure monitor for a total of 78 days during 9.6 months and starting 1 year after delivery. The data obtained oscillometrically for both longitudinal profiles were analyzed separately by multiple-component linear least-squares rhythmometry, a procedure used to describe the periodic waveform of nonsinusoidal rhythms. The analysis of blood pressure variability during pregnancy allows the identification not only of the circadian (with a period of 24 h), but also of other statistically significant components with periods of 156 (6.5 days, apparently free-running from the social week) and of 720 h (30 days) for both systolic and diastolic blood pressure. This multiharmonic time structure is somewhat different during menstruation in the same woman and during a similar time span, with statistically significant components of 96 h (4 days), 192 h (8 days), and 960 h (40 days) for both systolic and diastolic blood pressure. Moreover, the ratio between the amplitudes of the infradian components identified during pregnancy in clinical health is reversed from that obtained in women with preeclampsia. The complex time-structure of blood pressure during pregnancy offers new endpoints to be taken into account for an early identification of gestational hypertension or even preeclampsia.     

Multifrequency Infradian Variation of Blood Pressure During and After Human Pregnancy

We used a chronobiologic approach to explore the possibility that there may be -7-day (circaseptan) and -30-day (circatrigintan) components in blood pressure during a healthy human pregnancy, the amenorrhea of this status notwithstanding. The results were compared with those obtained from data longitudinally monitored on the same subject at a time when she was not pregnant. The woman under study used an ABPM-630 Colin (Komaki, Japan) device to monitor her blood pressures and heart rates at half to 1-h intervals, with few interruptions. During pregnancy, starting during the first gestational week, she monitored herself for 2 of each 6-day span for the entire duration of pregnancy (a total of 76 days of monitoring). Additionally, with a monitoring protocol similar to that during pregnancy, the subject used the same blood pressure monitor for a total of 78 days during 9.6 months and starting 1 year after delivery. The data obtained oscillometrically for both longitudinal profiles were analyzed separately by multiple-component linear least-squares rhythmometry, a procedure used to describe the periodic waveform of nonsinusoidal rhythms. The analysis of blood pressure variability during pregnancy allows the identification not only of the circadian (with a period of 24 h), but also of other statistically significant components with periods of 156 (6.5 days, apparently free-running from the social week) and of 720 h (30 days) for both systolic and diastolic blood pressure. This multiharmonic time structure is somewhat different during menstruation in the same woman and during a similar time span, with statistically significant components of 96 h (4 days), 192 h (8 days), and 960 h (40 days) for both systolic and diastolic blood pressure. Moreover, the ratio between the amplitudes of the infradian components identified during pregnancy in clinical health is reversed from that obtained in women with preeclampsia. The complex time-structure of blood pressure during pregnancy offers new endpoints to be taken into account for an early identification of gestational hypertension or even preeclampsia.     

Maternal Vitamin D Status in Preeclampsia: Seasonal Changes Are Not Influenced by Placental Gene Expression of Vitamin D Metabolizing Enzymes

Preeclampsia, a hypertensive disorder in pregnancy develops in 2–8% of pregnancies worldwide. Winter season and vitamin D deficiency have been associated with its onset.

Objective

To investigate the influence of season on maternal vitamin D status and placental vitamin D metabolism.

Methods

25-OH vitamin D and 1,25-(OH)₂ vitamin D were measured in maternal serum obtained during the winter or summer months from 63 pregnant women at delivery (43 healthy, 20 preeclampsia). In a subgroup, mRNA expression of CYP24A1 (24-hydroxylase), CYP27B1 (1α-hydroxylase) and VDR (vitamin D receptor) were quantified by real time PCR in placental samples of 14 women with normal pregnancies and 13 with preeclampsia.

Results

In patients with preeclampsia,25-OH vitamin D levels were lower, but differed significantly from controls only in summer (18.21±17.1 vs 49.2±29.2 ng/mL, P<0.001), whereas 1,25-(OH)₂ vitamin D levels were significantly lower only in winter (291±217 vs 612.3±455 pmol/mL, P<0.05). A two-factorial analysis of variance produced a statistically significant model (P<0.0001) with an effect of season (P<0.01) and preeclampsia (P = 0.01) on maternal 25-OH vitamin D levels, as well as a significant interaction between the two variables (P = 0.02). Placental gene expression of CYP24A1, CYP27B1, and VDR did not differ between groups or seasons. A negative correlation between placental gene expression of CYP24A1 and CYP27B1 was observed only in healthy controls (r = −0.81, P<0.0001).

Summary

Patients with preeclampsia displayed lower vitamin D serum levels in response to seasonal changes.The regulation of placental CYP24A1, but not of the VDR or CYP27B1 might be altered in preeclampsia.     

Pre-Conception Dyslipidemia Is Associated with Development of Preeclampsia and Gestational Diabetes Mellitus

IntroductionThe association between glucose intolerance, elevated blood pressure and abnormal lipid levels is well established and comprises the basis of metabolic syndrome pathophysiology. We hypothesize that abnormal preconception lipid levels are associated with the increased risk of severe pregnancy complications such as preeclampsia and gestational diabetes mellitus.MethodsWe included all singleton deliveries (n = 27,721) of women without known cardiovascular morbidity and preeclampsia and gestational diabetes mellitus during previous pregnancies. Association between preconception low high density lipoprotein cholesterol (HDLc level≤50 mg/dL), high triglycerides (level≥150 mg/dL) and the primary outcome (composite of gestational diabetes mellitus/or preeclampsia) was assessed using Generalized Estimation Equations.ResultsPrimary outcome of preeclampsia and/or gestational diabetes was observed in a total of 3,243 subjects (11.7%). Elevated triglycerides and low HDLc were independently associated with the primary outcome: with odds ratio (OR) of 1.61 (95% CI 1.29–2.01) and OR = 1.33 (95% CI 1.09–1.63), respectively, after adjusting for maternal age, weight, blood pressure, repeated abortions, fertility treatments and fasting glucose. There was an interaction between the effects of HDLc≤50 mg/dL and triglycerides≥150 mg/dL with an OR of 2.69 (95% CI 1.73–4.19).ConclusionsOur analysis showed an increased rate of preeclampsia and/or gestational diabetes in women with low HDLc and high triglycerides values prior to conception. In view of the severity of these pregnancy complications, we believe this finding warrants a routine screening for the abnormal lipid profile among women of a child-bearing age.     

妊娠高血压视网膜病变影响因素分析及血管内皮功能检测的临床意义

目的:探讨妊娠高血压视网膜病变的影响因素及血管内皮功能检测的临床意义。方法:前瞻性选取2017年1月~2018年12月期间湖北省妇幼保健院收治的150例妊娠高血压视网膜病变患者作为观察组,根据国际通用的Duker-Elder眼底分期标准分为Ⅰ期组69例,Ⅱ期组57例,Ⅲ期组24例。选取同时期该院收治的妊娠高血压无视网膜病变患者40例为对照组。采用酶联免疫吸附法检测血清胰岛素样生长因子(IGF-1)、内皮素-1(ET-1)水平,采用Pearson相关性分析IGF-1和ET-1水平与病变程度的相关性,采用多因素Logistic回归分析妊娠高血压视网膜病变的影响因素。结果:随着Duker-Elder眼底分期的增加,血清ET-1水平呈不断升高趋势,IGF-1水平呈不断下降趋势(P<0.05)。Pearson相关性分析显示,病变程度与血清IGF-1水平呈负相关,而与ET-1水平呈正相关(P<0.05)。单因素分析结果显示,妊娠高血压视网膜病变的发生与病程、孕周、血压、体质量、蛋白尿、红细胞压积有关(P<0.05),而与年龄无关(P>0.05)。Logistic回归分析结果显示,病程>3W、血压≥160/110 mm Hg、体质量>85kg、蛋白尿为+++、红细胞压积>0.35均是妊娠高血压视网膜病变发生的独立危险因素(P<0.05),而孕周>28W则是其保护因素(P<0.05)。结论:妊娠高血压视网膜病变患者存在IGF-1、ET-1的异常表达,且其表达水平与病变程度息息相关。血压、病程、蛋白尿、体质量、红细胞压积均是妊娠高血压视网膜病变发生的独立危险因素,孕周则是其保护因素。     

Is There an Association between Sleeping Patterns and Other Environmental Factors with Obesity and Blood Pressure in an Urban African Population?

Beyond changing dietary patterns, there is a paucity of data to fully explain the high prevalence of obesity and hypertension in urban African populations. The aim of this study was to determine whether other environmental factors (including sleep duration, smoking and physical activity) are related to body anthropometry and blood pressure (BP). Data were collected on 1311 subjects, attending two primary health care clinics in Soweto, South Africa. Questionnaires were used to obtain data on education, employment, exercise, smoking and sleep duration. Anthropometric and BP measurements were taken. Subjects comprised 862 women (mean age 41 ± 16 years and mean BMI 29.9 ± 9.2 kg/m²) and 449 men (38 ± 14 years and 24.8 ± 8.3 kg/m²). In females, ANOVA showed that former smokers had a higher BMI (p<0.001) than current smokers, while exposure to second hand smoking was associated with a lower BMI (p<0.001) in both genders. Regression analyses demonstrated that longer sleep duration was associated with a lower BMI (p<0.05) in older females only, and not in males, whilst in males napping during the day for > 30 minutes was related to a lower BMI (β = -0.04, p<0.01) and waist circumference (β = -0.03, p<0.001). Within males, napping for >30 minutes/day was related to lower systolic (β = -0.02, p<0.05) and lower diastolic BP (β = -0.02, p = 0.05). Longer night time sleep duration was associated with higher diastolic (β = 0.005, p<0.01) and systolic BP (β = 0.003, p<0.05) in females. No health benefits were noted for physical activity. These data suggest that environmental factors rarely collected in African populations are related, in gender-specific ways, to body anthropometry and blood pressure. Further research is required to fully elucidate these associations and how they might be translated into public health programs to combat high levels of obesity and hypertension.     

Association of Processed Meat Intake with Hypertension Risk in Hemodialysis Patients: A Cross-Sectional Study

In this cross-sectional study, we hypothesized that hemodialysis patients consuming greater processed meat is associated with hypertension risk, which can be partly explained by the high sodium content in processed meat. From September 2013 to May 2014, one hundred and four patients requiring chronic hemodialysis treatment were recruited from hemodialysis centers. Data on systolic blood pressure and diastolic blood pressure before receiving dialysis, and 3-day dietary records of the recruited patients were collected. HD patients with systolic and diastolic blood pressures greater than140 mmHg and higher than 90 mmHg, respectively, were considered hypertension risk. Protein foods were divided into 4 categories: red meat, white meat, soybeans, and processed meat (e.g., sausage and ham). In a model adjusted for energy intake and hypertension history, additional servings of processed meats was positively associated to systolic blood pressure >140 mmHg (odds ratio [95% confidence interval]: 2.1 [1.0–4.3]), and diastolic blood pressure > 90 mmHg (odds ratio: 2.5 [1.2–5.5]). After adjustment for dietary sodium contents or body mass index (BMI), most associations were substantially attenuated and were no longer significant. In systolic blood pressure greater than140 mmHg, one serving per day of red meats (β = -1.22, P < .05) and white meats (β = -0. 75, P = .05) was associated with a reduced risk compared with one serving per day of processed meats. Similarly, compared with one serving per day of processed meat, a reduced risk of diastolic blood pressure higher than 90 mmHg was associated with one serving per day of red meat (β = -1. 59, P < .05), white meat (β = -0. 62, P < .05). Thus, in these hemodialysis patients, intake of processed meat is significantly positively associated with higher blood pressure risk, and both sodium contents in processed meat and BMI significantly contributes to this association.     

A1M Ameliorates Preeclampsia-Like Symptoms in Placenta and Kidney Induced by Cell-Free Fetal Hemoglobin in Rabbit

Preeclampsia is one of the most serious pregnancy-related diseases and clinically manifests as hypertension and proteinuria after 20 gestational weeks. The worldwide prevalence is 3-8% of pregnancies, making it the most common cause of maternal and fetal morbidity and mortality. Preeclampsia lacks an effective therapy, and the only “cure” is delivery. We have previously shown that increased synthesis and accumulation of cell-free fetal hemoglobin (HbF) in the placenta is important in the pathophysiology of preeclampsia. Extracellular hemoglobin (Hb) and its metabolites induce oxidative stress, which may lead to acute renal failure and vascular dysfunction seen in preeclampsia. The human endogenous protein, α₁-microglobulin (A1M), removes cell-free heme-groups and induces natural tissue repair mechanisms. Exogenously administered A1M has been shown to alleviate the effects of Hb-induced oxidative stress in rat kidneys. Here we attempted to establish an animal model mimicking the human symptoms at stage two of preeclampsia by administering species-specific cell-free HbF starting mid-gestation until term, and evaluated the therapeutic effect of A1M on the induced symptoms. Female pregnant rabbits received HbF infusions i.v. with or without A1M every second day from gestational day 20. The HbF-infused animals developed proteinuria and a significantly increased glomerular sieving coefficient in kidney that was ameliorated by co-administration of A1M. Transmission electron microscopy analysis of kidney and placenta showed both intracellular and extracellular tissue damages after HbF-treatment, while A1M co-administration resulted in a significant reduction of the structural and cellular changes. Neither of the HbF-treated animals displayed any changes in blood pressure during pregnancy. In conclusion, infusion of cell-free HbF in the pregnant rabbits induced tissue damage and organ failure similar to those seen in preeclampsia, and was restored by co-administration of A1M. This study provides preclinical evidence supporting further examination of A1M as a potential new therapy for preeclampsia.     

A deficiency of placental IL-10 in preeclampsia.

Accommodation of the fetoplacental unit in human pregnancy requires maternal immune tolerance to this "semiallograft". Local antiplacental immunity is modified by synthesis of uncommon histocompatibility Ags (e.g., HLA-G), growth factors, and cytokines by the placenta. Placental interleukins have been identified in reproductive tissues, but their roles in adaptive maternal immunity and determining term pregnancy outcomes have not been fully clarified. This study examined the distribution of IL-10 and TNF-alpha staining in term placentas. Women with proteinuric hypertension (PE, n = 10) were compared with an age-matched group with normal pregnancy (NP, n = 14) and gestational hypertension (GH, n = 6). Using immunohistochemistry of parrafin-fixed tissues, trophoblast cells were identified by cytokeratin 7 and cytokeratin 18 staining. The cytokine binding of villous trophoblast cells was scored depending on the extent of circumferential cytoplasm staining (<25%; intermediate or >75%). The cytokine positive decidual cells were scored as a percentage of total extravillous trophoblast cells. There was a reduction in villous IL-10 immunostaining compared with normal term placenta (PE, 10.2 +/- 1.1, mean +/- SEM; NP, 14.07 +/- 1.16 Mann-Whitney U test; p = 0.02). In these patients, there was an increase in TNF-alpha immunostaining. Sparse endovascular extravillous trophoblast cells demonstrated nuclear IL-10 staining in 30% of patients with preeclampsia. Serum IL-10 was diminished in women with preeclampsia compared with normal pregnancy. In conclusion, villous trophoblast demonstrated diminished immunostaining of IL-10 in preeclampsia. This abnormality may be associated with heightened maternal antifetal immunity and therefore inadequate placental development in preeclampsia.     

Maternal Serum and Breast Milk Vitamin D Levels: Findings from the Universiti Sains Malaysia Pregnancy Cohort Study

Background

Vitamin D deficiency has become a global health issue in pregnant women. This study aimed to assess the adequacy of maternal vitamin D status by measuring maternal serum and breast milk 25-hydroxyvitamin D [25(OH)D] levels and to determine the association between maternal serum and milk 25(OH)D levels.

Methods

Data was obtained from the Universiti Sains Malaysia Pregnancy Cohort Study. This study was conducted from April 2010 to December 2012 in the state of Kelantan, Malaysia. Blood samples from pregnant women aged 19 to 40 years were drawn in the second and third trimesters of pregnancy, while breast milk samples at delivery, 2, 6 and 12 months postpartum were collected to analyze for 25(OH)D levels. A total of 102 pregnant women were included in the analysis.

Results

Vitamin D deficiency [25(OH)D <50 nmol/L] was detected in 60% and 37% of women in the second and third trimesters of pregnancy, respectively. There were 6% and 23% of women who reached normal level of vitamin D status in the second trimester and the third trimester, respectively. Multivitamin intakes during pregnancy were significantly associated with higher serum 25(OH)D levels in the second trimester (β = 9.16, p = 0.005) and the third trimester (β = 13.65, p = 0.003). 25(OH)D levels in breast milk during the first year of lactation ranged from 1.01 to 1.26 nmol/L. Higher maternal serum 25(OH)D level in the second trimester of pregnancy was associated with an elevated level of 25(OH)D in breast milk at delivery (β = 0.002, p = 0.026).

Conclusions

This study shows that high proportions of Malay pregnant women are at risk of vitamin D deficiency. Maternal vitamin D status in the second trimester of pregnancy was found to influence vitamin D level in breast milk at delivery.     

Report of the Canadian Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of hypertensive disorders in pregnancy

OBJECTIVE: To provide Canadian physicians with comprehensive, evidence-based guidelines for the nonpharmacologic management and prevention of gestational hypertension and pre-existing hypertension during pregnancy. OPTIONS: Lifestyle modifications, dietary or nutrient interventions, plasma volume expansion and use of prostaglandin precursors or inhibitors. OUTCOMES: In gestational hypertension, prevention of complications and death related to either its occurrence (primary or secondary prevention) or its severity (tertiary prevention). In pre-existing hypertension, prevention of superimposed gestational hypertension and intrauterine growth retardation. EVIDENCE: Articles retrieved from the pregnancy and childbirth module of the Cochrane Database of Systematic Reviews; pertinent articles published from 1966 to 1996, retrieved through a MEDLINE search; and review of original randomized trials from 1942 to 1996. If evidence was unavailable, consensus was reached by the members of the consensus panel set up by the Canadian Hypertension Society. VALUES: High priority was given to prevention of adverse maternal and neonatal outcomes in pregnancies with established hypertension and in those at high risk of gestational hypertension through the provision of effective nonpharmacologic management. BENEFITS, HARMS AND COSTS: Reduction in rate of long-term hospital admissions among women with gestational hypertension, with establishment of safe home-care blood pressure monitoring and appropriate rest. Targeting prophylactic interventions in selected high-risk groups may avoid ineffective use in the general population. Cost was not considered. RECOMMENDATION: Nonpharmacologic management should be considered for pregnant women with a systolic blood pressure of 140-150 mm Hg or a diastolic pressure of 90-99 mm Hg, or both, measured in a clinical setting. A short-term hospital stay may be required for diagnosis and for ruling out severe gestational hypertension (preeclampsia). In the latter case, the only effective treatment is delivery. Palliative management, dependent on blood pressure, gestational age and presence of associated maternal and fetal risk factors, includes close supervision, limitation of activities and some bed rest. A normal diet without salt restriction is advised. Promising preventive interventions that may reduce the incidence of gestational hypertension, especially with proteinuria, include calcium supplementation (2 g/d), fish oil supplementation and low-dose acetylsalicylic acid therapy, particularly in women at high risk for early-onset gestational hypertension. Pre-existing hypertension should be managed the same way as before pregnancy. However, additional concerns are the effects on fetal well-being and the worsening of hypertension during the second half of pregnancy. There is, as yet, no treatment that will prevent exacerbation of the condition. VALIDATION: The guidelines share the principles in consensus reports from the US and Australia on the nonpharmacologic management of hypertension in pregnancy.