Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies

Objective: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia. Study Design: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0-22.6 weeks']). Smoking status was determined by self-report. Results: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4-337.3] vs 95.9 [48.5-180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1-486.0] vs 152.2 [73.6-253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6-6.5] vs 6.8 [5.5-8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8-5.6] vs 5.3 [4.3-6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups. Conclusions: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort

Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PlGF) in Preeclampsia among High Risk Pregnancies

Background: Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome. Methods: This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF. Results: The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2- fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia. Conclusions: The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women

Bioinformatics Approach Reveals Evidence for Impaired Endometrial Maturation Before and During Early Pregnancy in Women Who Developed Preeclampsia

Impaired uterine invasion by extravillous trophoblast in early gestation is implicated in the genesis of preeclampsia, a potentially lethal malady of human pregnancy. However, reasons for extravillous trophoblast dysfunction remain unclear because of virtual inaccessibility of early placental and uterine tissues from women who develop preeclampsia, and the absence of animal models in which the disease spontaneously occurs. Consequently, the possibility that deficient or defective maturation of the endometrium (decidualization) may compromise extravillous trophoblast invasion in preeclampsia remains unexplored. Using a bioinformatics approach, we tested this hypothesis identifying 396 differentially expressed genes (DEG) in chorionic villous samples from women at ≈11.5 gestational weeks who developed severe preeclampsia symptoms 6 months later compared with chorionic villous samples from normal pregnancies. A large number, 154 or 40%, overlapped with DEG associated with various stages of normal endometrial maturation before and after implantation as identified by other microarray data sets (P=4.7×10−14). One-hundred and sixteen of the 154 DEG or 75% overlapped with DEG associated with normal decidualization in the absence of extravillous trophoblast, ie, late-secretory endometrium (LSE) and endometrium from tubal ectopic pregnancy (EP; P=4.2×10−9). Finally, 112 of these 154 DEG or 73% changed in the opposite direction in microarray data sets related to normal endometrial maturation (P=0.01), including 16 DEG upregulated in decidual (relative to peripheral blood) natural killer cells that were downregulated in chorionic villous samples from women who developed preeclampsia (P<0.0001). Taken together, these results suggest that insufficient or defective maturation of endometrium and decidual natural killer cells during the secretory phase and early pregnancy preceded the development of preeclampsia.Fil: Rabaglino, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto; ArgentinaFil: Post Uiterweer, Emiel D.. University of Utrecht; Países BajosFil: Jeyabalan, Arun. Magee Womens Hospital; Estados UnidosFil: Hogge, William A.. Magee Womens Hospital; Estados UnidosFil: Conrad, Kirk P.. University of Florida; Estados Unido

Effects of lactation on postpartum blood pressure among women with gestational hypertension and preeclampsia

BackgroundWomen with a history of hypertensive disorders of pregnancy are at an increased risk of hypertension and cardiovascular disease in later life. Lactation has been associated with a reduced risk of maternal hypertension, both in the postpartum period and later life. However, little is known about whether lactation is also cardioprotective in women with hypertensive disorders of pregnancy such as preeclampsia or gestational hypertension.ObjectiveThis study aimed to characterize the relationship between lactation and postpartum blood pressure among women with preeclampsia and gestational hypertension.Study designData were obtained from women who participated in the Prenatal Exposures and Preeclampsia Prevention study (n&nbsp;= 379; 66% African American; 85% overweight or obese). Women enrolled during pregnancy and attended a postpartum visit (on average, 9.1 months after delivery) during which data on lactation duration and blood pressure were collected. The significance of the associations between postpartum blood pressure and lactation among women who remained normotensive during pregnancy, developed gestational hypertension, or developed preeclampsia were assessed with an analysis of variance. Linear regression models were used to adjust for maternal age, race, education, prepregnancy weight, and time since delivery.ResultsGestational hypertension affected 42 subjects (11%) and preeclampsia affected 33 (9%). Lactation was reported by 217 (57%) with 78 (21%) reporting ≥ 6 months of lactation. Women who lactated were somewhat older, more educated, and had higher socioeconomic status. Among women who had gestational hypertension, lactation was associated with lower systolic blood pressure (P&nbsp;= .02) and diastolic blood pressure (P&nbsp;= .02). This association persisted after adjustment for age, race, education, prepregnancy weight, and time since delivery. However, for women who had preeclampsia and women who remained normotensive during pregnancy, lactation was not associated with postpartum blood pressure in either bivariate or multivariate analyses.ConclusionThis study found that lactation is associated with lower postpartum blood pressure among overweight women who develop gestational hypertension but not among women who develop preeclampsia. Future studies are needed to explore the association of lactation and blood pressure in later life for women with hypertensive disorders of pregnancy

An exploratory study of white blood cell proportions across preeclamptic and normotensive pregnancy by self-identified race in individuals with overweight or obesity

Objective: Examine white blood cell (WBC) proportions across preeclamptic (n = 28 cases) and normotensive (n = 28 controls) pregnancy in individuals with overweight/obesity. Methods: WBC proportions were inferred from genome-wide DNA methylation data and compared by case/control status and self-identified race. Results: In Trimester 1, ean B cell proportions were suggestively lower in cases in the overall sample and significantly lower in White participants but not in Black participants. More significant WBC proportion changes were observed across normotensive than preeclamptic pregnancy. Conclusions: These findings in a small sample demonstrate need for additional studies investigating the relationship between self-identified race and WBCs in pregnancy

Circulating pregnancy hormone relaxin as a first trimester biomarker for preeclampsia.

Objective: Preeclampsia, a multi-system hypertensive disorder, is associated with perturbations in the maternal cardiovascular system during early pregnancy. The corpus luteal hormone relaxin, a potent vasodilator, may contribute to physiological circulatory changes especially in early gestation when circulating levels are highest. This study investigated whether first trimester circulating relaxin may be a suitable biomarker for the early prediction of preeclampsia. Methods: Relaxin was initially measured in first-trimester samples of women who developed late-onset preeclamptic (LO-PE; delivery ≥ 34 weeks; n = 33) and uncomplicated pregnancies (n = 25) in Pittsburgh, USA. Subsequently, to expand the group numbers, relaxin was measured in women who developed LO-PE (n = 95), early-onset preeclamptic (EO-PE; delivery < 34 weeks; n = 57), and uncomplicated pregnancies (n = 469) in Utrecht, the Netherlands. Results: In the Pittsburgh subjects, low relaxin levels (lowest centile: <p10) showed an adjusted odds ratio (OR) of 5.29 (95%CI 1.10–25.5) for LO-PE. In the Utrecht population, low relaxin levels (<p10) demonstrated adjusted ORs of 1.45 (95%CI 0.54–3.90) and 2.03 (95%CI 1.06–3.88) for EO-PE and LO-PE respectively, the latter increasing to an adjusted OR of 3.18 (95%CI 1.41–7.20) when newborn weight was < 10%. Serum relaxin concentrations slightly improved the detection rate of a previously derived prediction model for LO-PE from 42.5% to 45.1% at a fixed 10% false-positive rate. Conclusion: Relaxin shows little improvement in the performance of first trimester prediction models, which does not support its clinical implementation as a biomarker. Although this study was only correlational, the results point to a possible pathophysiologic role f

Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies

Objective: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia.Study Design: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0–22.6 weeks']). Smoking status was determined by self-report.Results: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4–337.3] vs 95.9 [48.5–180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1–486.0] vs 152.2 [73.6–253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6–6.5] vs 6.8 [5.5–8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8–5.6] vs 5.3 [4.3–6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups.Conclusions: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort.</p