The use of digital peripheral artery tonometry to detect endothelial dysfunction in pregnant women who smoke.

OBJECTIVE: We hypothesized that, as has been shown outside of pregnancy, endothelial dysfunction would be seen in a dose-dependent fashion among women who smoke in the midtrimester of pregnancy. STUDY DESIGN: Endothelial function in women with singleton pregnancies between 16 and 23 weeks was analyzed utilizing the Endo-PAT2000 device (Itamar Medical Ltd., Caesarea, Israel) and expressed as a reactive hyperemia ratio (RHI). Serum was drawn to check cotinine and high-sensitivity C-reactive protein (CRP) levels. SAS 9.2 (SAS Institute, Cary, NC) was used to perform statistical tests including Student t test, analysis of variance, Fisher exact test, and Pearson coefficient. RESULTS: Endothelial function was noninvasively examined in 29 smokers and 31 nonsmokers. Demographics including age, race, and parity were similar between groups. Mean RHI was not significantly different between smokers and nonsmokers (1.43 ± 0.32 versus 1.53 ± 0.39, p = 0.27). No correlation was noted when cotinine values were plotted against RHI or CRP values in smokers (rho = 0.24, p = 0.21 and rho = 0.26, p = 0.18, respectively). RHI did correlate with diastolic blood pressure (rho = -0.40, p = 0.002), systolic blood pressure (rho = -0.35, p = 0.006), and heart rate (rho = -0.37, p = 0.004). CONCLUSION: We did not find an association between smoking status and endothelial dysfunction in the midtrimester utilizing a noninvasive methodology.

Extreme morbid obesity and labor outcome in nulliparous women at term.

We examined the prevalence of cesarean delivery (CD) among women with morbid obesity and extreme morbid obesity. Using Kentucky birth certificate data, a cross-sectional analysis of nulliparous singleton gestations at term was performed. We examined the prevalence of CD by body mass index (BMI; in kg/m2) using the National Institutes of Health/World Health Organization schema and a modified schema that separates extreme morbid obesity (BMI ≥ 50) from morbid obesity (BMI ≥ 40 to < 50). Bivariate and multivariate analyses were performed. Multivariate modeling controlled for maternal age, estimated gestational age, birth weight, diabetes, and hypertensive disorders. Overall, 83,278 deliveries were analyzed. CD was most common among women with a prepregnancy BMI ≥ 50 (56.1%, 95% confidence interval 50.9 to 61.4%). Extreme morbid obesity was most strongly associated with CD (adjusted odds ratio 4.99, 95% confidence interval 4.00 to 6.22). Labor augmentation decreased the likelihood of CD among women with extreme morbid obesity, but this failed to reach statistical significance. We speculate a qualitative or quantitative deficiency in the hormonal regulation of labor exists in the morbidly obese parturient. More research is needed to better understand the influence of morbid obesity on labor.

Violence against women and postpartum depression.

BACKGROUND: Violence against women (VAW), including intimate partner violence (IPV) in its various forms (sexual, physical, or stalking), and childhood violence (sexual or physical) are common and are associated with depressive symptoms. We examined the association between these violence exposures and self-reported history of postpartum depression (PPD). METHODS: Women from the Kentucky Women's Health Registry (KWHR) who reported at least one live birth were included in this study. Individual IPV and child abuse histories were examined for association with self-reported history of PPD. Multivariate regression analysis estimated adjusted risk ratios (aRR) and 95% confidence intervals (95% CI), controlling for age, obstetrical history, and substance abuse history. RESULTS: The 5380 women in the KWHR reporting at least one live birth were included in this study. Of these women, 2508 (46.6%) reported a history of any VAW. A history of adult VAW was associated with a history of PPD (aRR 1.48, 95% CI 1.12-1.95). Physical IPV (aRR 1.48, 95% CI 1.12-1.95) and stalking IPV (aRR 1.39, 95% CI1.03-1.87) were individually associated with PPD. Other types of violence were not individually associated with a history of PPD. The strength of association increased with each additional type of violence experienced (aRR1.17, 95% CI 1.06-1.30). CONCLUSIONS: Adult VAW is associated with self-reported history of PPD. With an increase in the number of types of abuse experienced, this association became stronger. Our findings highlight the need for thorough VAW screening in obstetrical populations.

Implications of type 2 diabetes on adolescent reproductive health risk: an expert model.

PURPOSE: The purpose of this article was to summarize scientific knowledge from an expert panel on reproductive health among adolescents with type 2 diabetes (T2D). METHODS: Using a mental model approach, a panel of experts--representing perspectives on diabetes, adolescents, preconception counseling, and reproductive health--was convened to discuss reproductive health issues for female adolescents with T2D. RESULTS: Several critical issues emerged. Compared with adolescents with type 1 diabetes, (1) adolescents with T2D may perceive their disease as less severe and have less experience managing it, putting them at risk for complications; (2) T2D is more prevalent among African Americans, who may be less trusting of the medical establishment; (3) T2D is associated with obesity, and it is often difficult to change one's lifestyle within family environments practicing sedentary and dietary behaviors leading to obesity; (4) teens with T2D could be more fertile, because obesity is related to earlier puberty; (5) although obese teens with T2D have a higher risk of polycystic ovary syndrome, which is associated with infertility, treatment with metformin can increase fertility; and (6) women with type 2 diabetes are routinely transferred to insulin before or during pregnancy to allow more intensive management. CONCLUSIONS: Findings from the expert panel provide compelling reasons to provide early, developmentally appropriate, culturally sensitive preconception counseling for teens with T2D.

A multicenter, randomized trial of treatment for mild gestational diabetes.

BACKGROUND: It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. METHODS: Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. RESULTS: A total of 958 women were randomly assigned to a study group--485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.14). There were no perinatal deaths. However, there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes, including mean birth weight (3302 vs. 3408 g), neonatal fat mass (427 vs. 464 g), the frequency of large-for-gestational-age infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and cesarean delivery (26.9% vs. 33.8%). Treatment of gestational diabetes mellitus, as compared with usual care, was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%; P=0.01). CONCLUSIONS: Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders. (ClinicalTrials.gov number, NCT00069576.)

Neonatal adiposity following maternal treatment of gestational diabetes with glyburide compared with insulin.

OBJECTIVE: We hypothesized that body composition would be similar among neonates of women with gestational diabetes (GDM) treated with glyburide or insulin. STUDY DESIGN: Women with GDM requiring medical therapy were randomized to insulin or glyburide. The primary outcome was percent neonatal fat mass measured by total body electrical conductivity. Secondary outcomes included anthropometrics, glycemic control, and biomarkers. Statistical analysis included Student t test, chi(2), and regression modeling. RESULTS: Eighty-two neonates underwent postnatal measurements. Baseline factors were not different by group. Neonatal percent fat mass did not differ between treatment groups (11.2 +/- 4.2 vs 12.8 +/- 5.7). Fat mass, body mass index, ponderal index, skinfold sum, and arm fat area were not different when analyzed by intent to treat or actual treatment group. Cord concentrations of biomarkers were also similar. CONCLUSION: There was no difference in neonatal adiposity in infants of women treated for GDM with glyburide or insulin.

First trimester adipocytokine concentrations and risk of developing gestational diabetes later in pregnancy.

OBJECTIVE: Adipocytokines are important regulators of insulin resistance. The aim of this study was to compare maternal adipocytokines in early pregnancy among women diagnosed with and without gestational diabetes (GDM) months later. DESIGN: A nested case-control study. PATIENTS: Adiponectin, resistin and interleukin-6 (IL-6) were measured in 59 nulliparous women (30 women with GDM and 29 controls) in plasma obtained in early pregnancy. Patients underwent routine testing for GDM in late pregnancy. MEASUREMENTS: Adiponectin was measured using radioimmunoassay. Resistin and IL-6 were measured by ELISA. Statistical analysis included Student's t-test, logistic regression and Pearson's correlation. RESULTS: Groups were not different by baseline descriptors or obstetric outcomes. Mean gestational age at sampling was 9.3 +/- 2.6 weeks. Adiponectin was lower (P < 0.001) in women who later developed GDM compared to controls (4.3 +/- 0.4 vs. 6.9 +/- 0.6 microg/ml). Adiponectin was negatively associated with the development of GDM (P = 0.002; OR: 0.70, 95% CI: 0.56, 0.88) and the association persisted in multivariable analysis controlling for confounders (P = 0.01; OR: 0.69, 95% CI: 0.52, 0.92). Women with first trimester adiponectin concentrations < 25th% were 10 times more likely to be diagnosed with GDM (OR 10.2; 95% CI 1.3, 78.7). Early adiponectin concentrations negatively correlated with BMI (P = 0.01; r = -0.32) and subsequent 50 g glucose challenge (P = 0.03; r =-0.29). Mean resistin and IL-6 concentrations were not different between the two groups. CONCLUSIONS: Women with GDM have evidence of altered adipocyte function as measured by adiponectin early in pregnancy, months before the clinical diagnosis of GDM is traditionally made.

Evidence of endothelial dysfunction in preeclampsia and risk of adverse pregnancy outcome.

The purpose of this study is to investigate whether endothelial dysfunction, as assessed by elevated cellular fibronectin (cFN), in women with preeclampsia is associated with an increased risk of preterm and/or small-for-gestational-age (SGA) births. Maternal plasma cFN was measured by enzyme-linked immunosorbent assay in samples collected at admission to delivery in 605 normotensive women, 171 women with transient hypertension, and 187 women with preeclampsia. Logistic regression was used to estimate the risk for preterm delivery, SGA, or both. Elevated cFN in women with preeclampsia was associated with an increased risk of both preterm and SGA births (odds ratio, 3.0; confidence interval [CI], 1.0-8.7) compared with women with preeclampsia without elevated cFN. The risk of preterm birth was 14.7-fold higher (CI, 8.1-26.7) and the risk of SGA was 6.8-fold higher (CI, 3.5-13.1) in women with preeclampsia, hyperuricemia, and elevated cFN compared with normotensive women. Elevated cFN is prevalent among women with preeclampsia and identifies women at increased risk of preterm delivery and SGA.

Metabolic changes in pregnancy.

Maternal metabolism changes substantially during pregnancy. Early gestation can be viewed as an anabolic state in the mother with an increase in maternal fat stores and small increases in insulin sensitivity. Hence, nutrients are stored in early pregnancy to meet the feto-placental and maternal demands of late gestation and lactation. In contrast, late pregnancy is better characterized as a catabolic state with decreased insulin sensitivity (increased insulin resistance). An increase in insulin resistance results in increases in maternal glucose and free fatty acid concentrations, allowing for greater substrate availability for fetal growth.

The effects of cigarette smoking on circulating maternal leukocytes during pregnancy.

During pregnancy, cigarette smoke exposure, a common environmental insult, is damaging to both mother and fetus and is associated with pregnancy loss. The mechanism underlying the pathophysiology of injury is not understood. We hypothesized that smoking during pregnancy interferes with the normal physiological adaptation of the maternal immune system. We used flow cytometry to measure changes in the distribution of subsets of circulating leukocytes and adhesion molecule expression in a prospective cohort of 198 women who had 325 blood samples obtained throughout pregnancy. Smoking status was assessed by plasma cotinine concentration. Smoking increased the frequency of CD3(+) lymphocytes and decreased CD56(+) cells at 14-20 weeks gestation. Smoking also decreased the expression of CD54 on monocytes and CD62L on granulocytes throughout pregnancy. Our data demonstrate that smoking affects several immune parameters, especially early in pregnancy. These perturbations may play a role in pregnancy loss in women who smoke.

Anatomic and functional changes of the upper urinary tract during pregnancy.

An appreciation of the maternal physiologic adaptations that occur in the renal system during pregnancy is fundamental to the understanding and proper clinical management of normal pregnancy, renal disorders in the gravid patient, and pregnancy-specific conditions such as pre-eclampsia. In this article, the authors first address the anatomic changes that occur in the upper urinary tract in normal pregnancy, followed by the dramatic alterations in maternal renal hemodynamics and glomerular filtration. They also briefly discuss renal handling of various substrates in pregnancy, including protein, uric acid, and glucose. An understanding of these changes is important and relevant to the clinician caring for pregnant women.

Preeclampsia activates circulating immune cells with engagement of the NF-kappaB pathway.

PROBLEM: Compelling evidence implicates peripheral immune activation in the pathophysiology of preeclampsia. Polymorphonuclear neutrophils appear to be the cells most strongly affected, with changes in expression of surface markers and release of granule enzymes. Here, we investigated activation in additional leukocyte populations among women with preeclampsia. METHOD: We used flow cytometry to evaluate changes in leukocyte markers in preeclampsia compared with uncomplicated pregnancy. To gain insights into intracellular pathways involved in leukocyte activation, we monitored the NF-kappaB signal transduction pathway. Plasma levels of interleukin-6 (IL-6) were also studied as an additional indication of cellular activation. RESULTS: Preeclampsia is associated with changes in L-selectin (CD62L) on neutrophils (P = 0.004), monocytes (P = 0.013), and T cells (P = 0.048) when compared with normal pregnancy. These changes include an increase in nuclear translocation of NF-kappaB and increased levels of IL-6 (P = 0.005). CONCLUSIONS: These findings are consistent with the presence of a generalized phenomenon of immune activation in preeclampsia.

Intracellular adhesion molecule concentrations in women who smoke during pregnancy.

OBJECTIVE: Smoking and endothelial dysfunction are associated with adverse pregnancy outcomes. The effect of smoking on vascular endothelium during pregnancy has not been well studied. Our objectives were to determine if smoking has an impact on endothelial function in pregnancy by comparing markers of endothelial function and to evaluate the contribution from different cellular sources. METHODS: We measured markers of endothelial function in a prospective cohort of 198 primiparous women who had 325 plasma samples obtained throughout pregnancy. Samples were assayed for intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. Smoking status was determined by serum cotinine concentration. Analyses of adhesion molecules were performed for 4 gestational age intervals by using Mann-Whitney and Kruskal-Wallis tests. Gene expression for ICAM-1 was determined by real-time polymerase chain reaction from placental biopsies. A human umbilical vein endothelial cell (HUVEC) culture model was utilized to evaluate the effect of cotinine on endothelial cell production of ICAM-1. RESULTS: ICAM-1 is increased, VCAM-1 was not different, and E-selectin was decreased among smokers at various times during pregnancy. Placental production of ICAM-1 was decreased in women who smoked (P = .02) as measured by real-time polymerase chain reaction. Human umbilical vein endothelial cells production of ICAM-1 increased with heavy concentrations of cotinine exposure (P < .01). CONCLUSION: Smoking during pregnancy is associated with vascular perturbations, as evidenced by increased concentrations of serum ICAM-1. It appears unlikely that the source of the increased ICAM-1 is the placenta. The endothelium most likely contributes to increased maternal ICAM-1 in heavy smokers, but a leukocyte source cannot be ruled out. LEVEL OF EVIDENCE: II-2.

Factors that affect maternal insulin resistance and modify fetal growth and body composition.

Fetal growth is multifactorial and can be altered by a variety of extrinsic and intrinsic factors. The maternal, placental, and fetal contribution to growth must all be considered. Of particular interest are maternal metabolic regulation and the availability of nutrients to the developing fetus. Weight gain, hyperlipidemia, and insulin resistance occur as a normal adaptation to pregnancy. Obesity and underlying insulin resistance among women of reproductive age are rapidly increasing, and the contribution of pregnancy on this abnormal metabolic background poses additional maternal and fetal challenges. Many components of the metabolic syndrome have been associated with changes in fetal growth, including obesity, dyslipidemia, hypertension, and insulin resistance or glucose intolerance. Additional factors affect fetal growth and include diet, exercise, and smoking. In this review, we briefly discuss the importance and descriptions of fetal growth, followed by a discussion of several of the extrinsic and intrinsic established factors affecting fetal growth. We highlight factors that may modify fetal growth and body composition directly or indirectly through alterations in maternal metabolism.

Uric acid is as important as proteinuria in identifying fetal risk in women with gestational hypertension.

Gestational hypertension is differentiated into higher and lower risk by the presence or absence of proteinuria. We asked if hyperuricemia, a common finding in pregnancy hypertension, might also be an indicator of increased risk. We examined fetal outcome data from 972 pregnancies collected from 1997 to 2002 in a nested case-control study. Participants were nulliparous with no known medical complications. The frequency of preterm birth, the duration of pregnancy, frequency of small-for-gestational-age infants, and birth weight centile were determined for pregnancies assigned to 8 categories by the presence or absence of combinations of hypertension, hyperuricemia, and proteinuria. In women with gestational hypertension, hyperuricemia was associated with shorter gestations and smaller birth weight centiles and increased risk of preterm birth and small-for-gestational-age infants. Hyperuricemia increased the risk of these outcomes in the presence or absence of proteinuria. Risk was also increased in a small group of women with hyperuricemia and proteinuria without hypertension. Women with only hypertension and hyperuricemia have similar or greater risk as women with only hypertension and proteinuria. Those with hypertension, proteinuria, and hyperuricemia have greater risk than those with hypertension and proteinuria alone. The risk of these outcomes increased with increasing uric acid. Hyperuricemia is at least as effective as proteinuria at identifying gestational hypertensive pregnancies at increased risk. Uric acid should be reexamined for clinical and research utility.

Effect of smoking on uric acid and other metabolic markers throughout normal pregnancy.

OBJECTIVES: Smoking, pregnancy, and preeclampsia are all associated with changes in markers of the metabolic syndrome. Several markers are increased in all three conditions. However, smoking is negatively associated with preeclampsia, and therefore some markers would be expected to behave differently in smokers during pregnancy. We compared several metabolic markers of the metabolic syndrome in healthy primigravid smokers and nonsmokers over normal pregnancy to explore mechanisms for the reduced risk of preeclampsia in smokers. STUDY DESIGN: Plasma was obtained from 63 women throughout pregnancy who delivered at term. Smoking status was determined by urinary cotinine concentrations measured by HPLC. Uric acid, creatinine, free fatty acids, triglycerides, and total cholesterol were measured with diagnostic kits. Data were analyzed by repeated-measures ANOVA. RESULTS: The smoking groups were not different by delivery gestational age, maternal age, body mass index, or race. Uric acid, cholesterol, and triglyceride concentrations increased during pregnancy (significant for time, P < 0.0001). Mean uric acid and creatinine concentrations were different by smoking status (P < 0.001 and P = 0.046). Nonsmokers had the lowest concentrations of uric acid, and women who quit smoking had the highest concentrations. Uric acid concentrations remained significantly different controlling for serum creatinine CONCLUSIONS: Women have changes in markers of the metabolic syndrome during pregnancy, and uric acid is further influenced by smoking. The difference in uric acid concentrations by smoking status may be secondary to increased production through the xanthine oxidase pathway but is not simply a result of altered glomerular function because the association persists after controlling for creatinine.

Second pregnancy outcomes following preeclampsia in a first pregnancy.

OBJECTIVES: We compared second pregnancy outcomes among women with and without preeclampsia in their first pregnancies who all had second pregnancies without preeclampsia. METHODS: One hundred thirty women with and 6148 without preeclampsia in their first pregnancies, who all had nonpreeclamptic second pregnancies, were included. Outcomes, including delivery gestational age, birthweight, small-for-gestational-age (SGA), and preterm delivery were compared. RESULTS: Overall, second pregnancy outcomes were not different between women with and without preeclampsia in their first pregnancy. However, when women were stratified by gestational timing of preeclampsia, women with preeclampsia at < 34 weeks (N = 22) had smaller infants and delivered earlier in their second nonpreeclamptic pregnancy compared to women with later preeclampsia (N = 108) or no preeclampsia in the first pregnancy. Women with early preeclampsia also had an increased risk of prematurity (< 37 weeks) in second pregnancies that persisted after controlling for confounding factors [Odds ratio (OR = 3.2)]. DISCUSSION: Second, nonpreeclamptic pregnancy outcomes are different between women with previous early preeclampsia and controls but not between late preeclampsia and controls. These findings support other epidemiological data indicating differences between early and late onset preeclampsia as well as a potential relationship of preeclampsia and spontaneous preterm birth.

Smoking during pregnancy is associated with alterations in markers of endothelial function.

OBJECTIVE: Alterations in endothelial function may explain the reduced risk of preeclampsia that is associated with smoking. We hypothesized that markers of endothelial function increase over pregnancy but decrease with smoking. STUDY DESIGN: Plasma samples were obtained throughout pregnancy from 63 primiparous women with normal pregnancies. The samples were assayed for cellular fibronectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1. Smoking status was determined by urinary cotinine concentrations. RESULTS: Mean cellular fibronectin concentrations were different by time (P<.001) and smoking status (P=.01); the lowest concentrations were found in smokers. In contrast, intracellular adhesion molecule-1 was different by smoking status (P=.046); the highest concentrations were found in smokers. Vascular cell adhesion molecule-1 was different over time (P<.001), but not by smoking status. CONCLUSION: Smoking during pregnancy is associated with reduced cellular fibronectin and increased intracellular adhesion molecule-1. These differences may be the result of different aspects of endothelial function or the source of the marker. The explanation for reduced preeclampsia in smokers remains elusive.

Plasma homocysteine and malondialdehyde are correlated in an age- and gender-specific manner.

Homocysteine is an independent risk factor for peripheral vascular and coronary artery disease. The exact mechanism by which homocysteine promotes vascular dysfunction is unclear, but it is speculated to involve oxidative stress. Several studies have investigated the role of homocysteine in promoting oxidative stress and have obtained conflicting results. The age and gender of the subject populations in these studies may have influenced the outcome. Therefore, we investigated whether plasma homocysteine concentrations were correlated with plasma malondialdehyde (MDA, a marker of oxidative stress), and if the subject's age and gender affected this correlation. Plasma homocysteine and MDA were measured in 35 premenopausal women, 14 young men, 38 postmenopausal women, and 18 older men. Homocysteine was significantly higher in men than women (P <.01) and in older subjects versus younger. However, MDA was significantly greater only in the young men (P <.01). Furthermore, there was a significant correlation between homocysteine and MDA only in these young men (R(2) = 0.50, P <.01). Lastly, subjects undergoing a methionine load did not exhibit increased MDA despite significant increases in homocysteine. Since oxidative stress correlates with basal homocysteine only in young men and does not increase with acutely increased homocysteine, it is unlikely to be the result of a direct effect of homocysteine.