Background: Obesity in pregnancy is increasing and is a risk factor for metabolic pathology such as preeclampsia. In the nonpregnant, obesity is associated with dyslipidemia, vascular dysfunction, ...and low-grade chronic inflammation.
Aim: Our aim was to measure microvascular endothelial function in lean and obese pregnant women at intervals throughout their pregnancies and at 4 months after delivery. Plasma markers of endothelial function, inflammation, and placental function and their association with microvascular function were also assessed.
Methods: Women in the 1st trimester of pregnancy were recruited, 30 with a body mass index (BMI) less than 30 kg/m2 and 30 with a BMI more than or equal to 30 kg/m2 matched for age, parity, and smoking status. In vivo endothelial-dependent and -independent microvascular function was measured using laser Doppler imaging in the 1st, 2nd, and 3rd trimesters of pregnancy and at 4 months postnatal. Plasma markers of endothelial activation soluble intercellular cell adhesion molecule-1 (sVCAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF), and plasminogen activator inhibitor (PAI)-1, inflammation (IL-6, TNFα, C-reactive protein, and IL-10), and placental function (PAI-1/PAI-2 ratio) were also assessed at each time point.
Results: The pattern of improving endothelial function during pregnancy was the same for lean and obese, but endothelial-dependent vasodilation was significantly lower (P < 0.05) in the obese women at each trimester (51, 41, and 39%, respectively). In the postpartum period, the improvement in endothelial-dependent vasodilation persisted in the lean women but declined to near 1st trimester levels in the obese (lean/obese difference, 115%; P < 0.01). There was a small but significant difference in endothelial-independent vasodilation between the two groups, lean response being greater than obese (P = 0.021), and response declined in both groups in the postpartum period. In multivariate analysis, time of sampling had the most impact on endothelial-independent function 18.5% (adjusted sum of squares expressed as a percentage of total means squared), P < 0.001 for sodium nitroprusside response; 9.8%, P < 0.001 for acetylcholine response, and obesity had the most impact on endothelial-dependent microvascular function (1.7%, P = 0.046 for sodium nitroprusside response; 19.3%, P < 0.001 for acetylcholine response). Time of sampling (11.2%, P < 0.001), IL-6 (4.0%, P = 0.002), and IL-10 (2.4%, P = 0.018) were significant independent contributors to variation in endothelial-dependent microvascular function. When obesity was entered into the model, the association with IL-6 and IL-10 was no longer significant, and obesity explained 6.8% (P < 0.001) of the variability in endothelial-dependent microvascular function. In the 1st trimester, obese women had a significantly higher PAI-1/PAI-2 ratio obese median (interquartile range), 0.87 (0.54–1.21) vs. lean 0.30 (0.21–0.47), P < 0.001), reflecting the lower PAI-2 levels in obese pregnant women. In a multivariate analysis, 1st trimester BMI (7.6%, P = 0.012), IL-10 (8.2%, P < 0.001), and sVCAM-1 (0.73%, P = 0.007) contributed to the 1st trimester PAI-1/PAI-2 ratio.
Conclusion: Obese mothers have a lower endothelium-dependent and -independent vasodilation when compared with lean counterparts. There was a higher PAI-1/ PAI-2 ratio in the 1st trimester in obese women, which improved later in pregnancy. Obese pregnancy is associated with chronic preexisting endothelial activation and impairment of endothelial function secondary to increased production of inflammatory T-helper cells-2 cytokines.
Abstract
Context
Maternal body mass index (BMI) is associated with increased birth weight but does not explain all the variance in fetal adiposity.
Objective
To assess the contribution of maternal ...body fat distribution to offspring birth weight and adiposity.
Design
Longitudinal study throughout gestation and at delivery.
Setting
Women recruited at 12 weeks of gestation and followed up at 26 and 36 weeks. Cord blood was collected at delivery.
Patients
Pregnant women (n = 45) with BMI 18.0 to 46.3 kg/m2 and healthy pregnancy outcome.
Methods
Maternal first trimester abdominal subcutaneous and visceral adipose tissue thickness (SAT and VAT) was assessed by ultrasound.
Main Outcome Measures
Maternal body fat distribution, maternal and cord plasma glucose and lipid concentrations, placental weight, birth weight, and fetal adiposity assessed by cord blood leptin.
Results
VAT was the only anthropometric measure independently associated with birth weight centile (r2 adjusted 15.8%, P = .002). BMI was associated with trimester 2 and trimesters 1 through 3 area under the curve (AUC) glucose and insulin resistance (Homeostatic Model Assessment). SAT alone predicted trimester 2 lipoprotein lipase (LPL) mass (a marker of adipocyte insulin sensitivity) (11.3%, P = .017). VAT was associated with fetal triglyceride (9.3%, P = .047). Placental weight was the only independent predictor of fetal adiposity (48%, P < .001). Maternal trimester 2 and AUC LPL were inversely associated with fetal adiposity (r = -0.69, P = .001 and r = -0.58, P = .006, respectively).
Conclusions
Maternal VAT provides additional information to BMI for prediction of birth weight. VAT may be a marker of reduced SAT expansion and increased availability of maternal fatty acids for placental transport.
•ST612-MRSA in Australia form distinct equine/veterinarian-associated and human-associated clades.•Bacteraemia-causing ST612-MRSA isolate in Western Australia is of the equine and ...veterinarian-associated ST612 clade.•ST612-MRSA is closely related to ST8 USA500 and carries conserved insertion sequences in virulence-modulating genes.•Rifampicin use in equine veterinary practice may encourage colonisation of horses by ST612-MRSA.
Staphylococcus aureus is a serious human and animal pathogen. Multilocus sequence type 612 (ST612) is the dominant methicillin-resistant S. aureus (MRSA) clone in certain South African hospitals and is sporadically isolated from horses and horse-associated veterinarians in Australia. Colonisation and infection by ST612-MRSA is increasing in Western Australia. Whole-genome sequencing was performed for 51 isolates of ST612-MRSA from Western Australian patients and healthcare workers, South African hospital patients, Australian veterinarians and New South Wales horses. Core genome phylogenies suggested that Australian equine and veterinarian-associated ST612-MRSA were monophyletic. Individual Western Australian isolates grouped either with this equine-associated lineage or more diverse lineages related to those in South African hospitals. Bioinformatic analyses of the complete ST612-MRSA reference genome SVH7513 confirmed that ST612-MRSA was closely related to ST8 USA500 MRSA. Common use of rifampicin in South Africa and equine veterinarian practice may favour ST612-MRSA in these settings. Humans and horses colonised with ST612-MRSA are potential reservoirs for MRSA in Australia.
Obesity is increasing in prevalence worldwide and in all age groups. In nonpregnant individuals, obesity is associated with dyslipidemia; hyperinsulinemia; vascular dysfunction; and, more recently, ...low-grade chronic inflammation. However, whether such effects are sustained during pregnancy has been sparsely investigated but is important to establish, given the association of maternal obesity with numerous adverse metabolic and vascular consequences.
We consecutively recruited 47 healthy women in the third trimester of pregnancy and divided the participants into 2 groups, lean n = 24; median body mass index (BMI), 22.1 kg/m2 and obese (n = 23; median BMI, 31.0 kg/m2) around the median first trimester BMI. The age, parity, and smoking history were comparable in both groups. A detailed panel of metabolic and inflammatory parameters was measured and an in vivo assessment of endothelial-dependent and -independent microvascular function made using laser doppler imaging. Although low-density lipoprotein cholesterol and glycosylated hemoglobin were similar, fasting triglyceride concentrations were higher 2.70 (interquartile range, 2.3–3.21) vs. 2.20 (IQ range, 2.0–2.6) mmol/liter, P = 0.02 and high-density lipoprotein concentrations were lower 1.55 (IQ range, 1.1–1.7) vs. 1.72 (IQ range, 1.4–2.0) mmol/liter, P = 0.02 in the obese group. Leptin 55.6 (range, 45–64.4) ng/ml vs. 23.8 (range, 13.2–35.2) ng/ml, P < 0.0001 and fasting insulin 14.5 (range, 11.4–27.3) vs. 6.5 (range, 4.6–9.7) mU/liter, P < 0.0001 levels were more than double. Similarly, levels of inflammatory parameters, IL-6 3.15 (range, 2.4–3.5) vs. 2.1 (range, 1.73–2.85) pg/ml, P = 0.003, and sensitive C-reactive protein 4.45 (range, 2.9–6.6) vs. 2.25 (range, 0.92–3.65) mg/ml, P = 0.0015 were also substantially elevated. Both endothelial-dependent and -independent vasodilatory responses were significantly reduced in the obese group (P = 0.0003 and P = 0.02, respectively, ANOVA) and systolic blood pressure was higher (P = 0.01). Metabolic factors, C-reactive protein (r = 0.289, P = 0.049), and insulin (r = 0.339, P = 0.02) were related inversely to endothelial-dependent function.
These comprehensive data demonstrate that, as in nonpregnant obese individuals, obesity in pregnancy is associated not only with marked hyperinsulinemia (without necessarily glucose dysregulation) and dyslipidemia but also impaired endothelial function, higher blood pressure, and inflammatory up-regulation. Such a spectrum of risk factors may contribute to maternal complications in obese women and, as a result, influence fetal programming of adult vascular disease. Clearly, these data provide further rationale to examine the potential benefits of preconceptual weight loss and antenatal exercise.
Preeclampsia is characterized by hypertension, dyslipidemia, and increased systemic inflammatory response and has been associated with an increased maternal risk of cardiovascular disease later in ...life. Low-grade chronic inflammation is a risk factor for cardiovascular disease. This study examined changes in inflammatory markers prospectively during pregnancy, the current inflammatory status of women who had a pregnancy complicated by preeclampsia 20 years previously against matched controls, and the association between inflammatory genes and risk of preeclampsia in a case (n=106) control (n=212) study. In control pregnancies (n=34), mean interleukin-10 (IL-10) levels increased 38% (P=0.012) and tumor necrosis factor-α (TNF-α) by 33% (P=0.024) between the first and third trimesters. The mean preeclampsia group IL-10 and TNF-α rose by 43% (P=0.013 and P=0.0065, respectively) from the first to the third trimester. In women with preeclampsia only, plasma IL-6 increased from the first to the third trimester (1.66 2.04 to 2.94 2.47 pg/mL; P=0.0004). Twenty years after the index pregnancy, women who had had preeclampsia demonstrated significantly higher IL-6 to IL-10 ratio (3.96 6.07 versus 2.12 1.89; P=0.034) compared with a healthy index pregnancy 20 years previously, that persisted after adjustment for smoking and current body mass index. The IL-1β (C-511T), IL-6 (G-174C), TNF-α (G-308A), E-selectin (S128R), intercellular adhesion molecule-1 (K469E), and C-reactive protein (C1059G) polymorphisms were not associated with risk of developing preeclampsia. In conclusion, preeclampsia is associated with short- and long-term changes in inflammatory status.
Summary Rates of obesity among the pregnant population have increased substantially and adiposity has a damaging effect on every aspect of female reproductive life. This review summarises ...epidemiological data concerning obesity-related complications of pregnancy. Obesity is linked to a number of adverse obstetric outcomes as well as increased maternal and neonatal morbidity and mortality. These complications include miscarriage, congenital abnormalities, pre-eclampsia, gestational diabetes mellitus, iatrogenic preterm delivery, postdates pregnancy with increased rates of induction of labour, caesarean section, postpartum haemorrhage, shoulder dystocia, infection, venous thromboembolism, and increased hospital stay. It is important to consider obese pregnant women as a high risk group with a linear increase in risk of complications associated with their degree of obesity. Their obstetric management should be consultant-led and involve a multidisciplinary team approach to improve outcome.
ABSTRACT—Adiponectin is a recently identified, insulin-sensitizing and anti-inflammatory protein released by adipocytes, which is paradoxically reduced in obesity. It suppresses endothelial ...activation. Physiological insulin resistance occurs in normal pregnancy and is exaggerated in women with preeclampsia (PE), together with enhanced inflammatory and endothelial activation. Women with increased body mass index (BMI) and insulin resistance are predisposed to PE. We hypothesized that adiponectin concentrations are reduced in normal pregnancy compared with postpartum values and further reduced in women with PE. Fifteen women with PE and 30 control subjects with similar first trimester BMI had adiponectin concentrations measured in the third trimester; postpartum measurements were repeated in 16 control subjects. Adiponectin concentration in healthy pregnant women correlated inversely with early pregnancy BMI (r =−0.47, P =0.01) and fasting insulin concentrations (r =−0.58, P =0.001). However, adiponectin concentrations did not differ significantly in pregnancy and postpartum samples (mean change, −0.15 μg/mL; 95% CI, −2.28 to 1.98, P =0.88). Plasma adiponectin concentrations were markedly elevated (P =0.01) in women with PE (mean, 21.6; SD, 8.18 μg/mL) compared with control subjects (mean, 14.7; SD, 7.06 μg/mL). Moreover, in PE, adiponectin concentrations did not correlate with first trimester BMI or insulin or with serum urate or creatinine concentrations or urinary protein levels. We conclude that plasma adiponectin concentrations are not elevated in normal human pregnancy and paradoxically elevated (by 47%) in women with PE. This may be secondary to exaggerated nonspecific adipocyte lipolysis or as a physiological response to enhance fat utilization and attenuate endothelial damage. Future studies should determine whether adiponectin concentrations help improve prediction of PE.
Context:
Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal-weight pregnant women, higher triglyceride ...is associated with increased small, dense low-density lipoprotein (LDL).
Hypothesis:
In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low-density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase.
Design:
Women (n = 55) of body mass index of 18–46 kg/m2 were sampled longitudinally at 12, 26, and 35 weeks' gestation and 4 months postnatally.
Setting:
Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite.
Outcome Measures:
Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined.
Results:
Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1–3 incremental area under the curve) was positively associated with plasma triglyceride response (r2 adjusted 25%, P < .001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal-weight women mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P = .014, and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P = .013).
Conclusions:
Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.
Epidemiological studies have recently demonstrated a relationship between pre‐eclampsia and coronary heart disease. Insulin resistance has been implicated as a common factor. We have demonstrated, ...for the first time, using laser Doppler imaging in vivo, impaired microvascular function in women 15–25 years following a pregnancy complicated by pre‐eclampsia. Thus, microvascular dysfunction, which is associated with insulin resistance, may be a predisposing vascular mechanism for both coronary heart disease and pre‐eclampsia. Pregnancies complicated by pre‐eclampsia may identify women at risk of vascular disease in later life and may provide the opportunity for lifestyle and risk factor modification to alter maternal vascular disease risk.
Summary
In an attempt to reduce the incidence of pregnancy associated venous thromboembolism (PA-VTE), some researchers have advocated screening of all women for the factor V
Leiden
mutation during ...early pregnancy. We have conducted a large retrospective study (over 72,000 deliveries) to determine if this would be useful. Sixty-two objectively confirmed venous thrombotic events (51 DVT, 11 PE) were recorded at two maternity units in the UK. The incidence of DVT was 0.71 per 1000 deliveries (95% CI 0.5-0.9) with 0.50 occurring in the antenatal period (95% CI 0.34-0.66) and 0.21 in the puerperium (95% CI 0.11-0.31). The incidence of PE was 0.15 per 1000 deliveries (95% CI 0.06-0.24), 0.07 antenatal (95% CI 0.01-0.13) and 0.08 in the puerperium (95% CI 0.02-0.14). Of these 62,50 attended for follow-up and thrombophilia screening. 28% of all episodes of PA-VTE had no CIinical risk factor for thrombosis or an identifiable thrombophilic abnormality. Deficiency of antithrombin was identified in 12% of individuals (95% CI 3-21) and the factor V
Leiden
mutation in 8% (95% CI 0.5-15.5). Based on estimates of the prevalence of the factor V
Leiden
mutation in the population, we estimate that the thrombotic risk for a woman during pregnancy or the puerperium with the defect is approximately 1 in 400-500. This figure would not lend support to the idea of random screening for the mutation in early pregnancy.
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