Maternal cardiac adaptation to subsequent pregnancy in formerly pre-eclamptic women according to recurrence of pre-eclampsia.

OBJECTIVES: Left-ventricular remodeling in women with pre-eclampsia (PE) is concentric rather than eccentric, and tends to persist postpartum, particularly after early-onset PE. This study was designed to determine whether prepregnancy cardiac geometry and function along with cardiac adaptation to the subsequent pregnancy in former early-onset PE patients differs between those who do and those who do not develop recurrent PE later on in their second pregnancy. METHODS: In 51 women with a history of early-onset PE, we performed serial cardiac ultrasound examinations and recorded automated measurements of blood pressure/heart rate before pregnancy and again at three consecutive times in the first half of their subsequent pregnancy. From the hospital records, we retrieved information on pregnancy outcome. We compared intergroup differences in cardiac indices using independent samples t-test, and intergroup differences in prepregnant cardiac ultrasound indices and subsequent pregnancy-induced cardiac adaptive response using repeated-measures ANOVA. RESULTS: PE recurred in 14/51 (27%) women. Preconception, the recurrent-PE group differed from the non-recurrent-PE group by having a lower left-ventricular mass (LVM) index (28 vs 32 g/m(2.7) , P < 0.05) and stroke volume (68 vs 77 mL, P < 0.05), and a higher resting heart rate (71 vs 64 bpm, P < 0.05). Despite these prepregnancy differences, the pregnancy-induced pattern of cardiac adaptive response was comparable in the two subgroups. After excluding hypertensive women, prepregnancy values for the LVM index remained significantly lower in the recurrent-PE group. CONCLUSIONS: Women with recurrent PE differed from the non-recurrent-PE group by having a lower LVM index and stroke volume, and a higher heart rate, but they responded to their subsequent pregnancy with a similar pattern of cardiac adaptation.

Formerly eclamptic women have lower nonpregnant blood pressure compared with formerly pre-eclamptic women: a retrospective cohort study.

OBJECTIVE: To compare nonpregnant blood pressure and circulating metabolic factors between formerly pre-eclamptic women who did and did not deteriorate to eclampsia. DESIGN: Retrospective observational cohort study. SETTING: Tertiary referral centre. POPULATION: Formerly pre-eclamptic women with (n = 88) and without (n = 698) superimposed eclampsia. METHODS: Women who experienced pre-eclampsia with or without superimposed eclampsia during their pregnancy or puerperium were tested for possible underlying cardiovascular risk factors at least 6 months postpartum. We measured blood pressure and determined cardiovascular and metabolic risk markers in a fasting blood sample. Groups were compared using Mann-Whitney U test, Spearman's Rho test or Fisher's Exact test (odds ratios). MAIN OUTCOME MEASURES: Differences in postpartum blood pressures and features of the metabolic syndrome between formerly pre-eclamptic and formerly eclamptic women. RESULTS: Formerly pre-eclamptic women who developed eclampsia differed from their counterparts without eclampsia by a lower blood pressure (P < 0.01) with blood pressure correlating inversely with the likelihood of having experienced eclampsia (P < 0.001). In addition, formerly eclamptic women had higher circulating C-reactive protein levels than formerly pre-eclamptic women (P < 0.05). All other circulating metabolic factors were comparable. Finally, 40% of all eclamptic cases occurred in the puerperium. CONCLUSIONS: Formerly pre-eclamptic women with superimposed eclampsia have lower nonpregnant blood pressure compared with their counterparts without neurological sequelae with blood pressure negatively correlated to the occurrence of eclampsia. As about 40% of all eclamptic cases occur postpartum, routine blood pressure monitoring postpartum should be intensified.

Early pregnancy circulatory adaptation and recurrent hypertensive disease: an explorative study.

INTRODUCTION: Hypertensive pregnancy disorders are assumed to be preceded by defective spiral artery remodeling. Whether this localized aberration at the implantation site affects the initial maternal systemic cardiovascular and renal adaptation to pregnancy is unclear. We explored in a high-risk population, whether the initial systemic maternal adaptation to pregnancy differs between women who do and do not develop a recurrent hypertensive disorder later on in pregnancy. METHODS: We enrolled 61 normotensive women with a previous hypertensive disorder of pregnancy and subdivided them into 2 subgroups, based on whether or not their next pregnancy remained uneventful (n = 33) or became complicated by a recurrent hypertensive disorder (n = 28). We measured before pregnancy and again at 18 ± 2 weeks of gestation cardiac output, blood pressure, plasma volume, creatinine clearance, and calculated total peripheral vascular resistance from cardiac output and blood pressure. RESULT: Both subgroups responded to pregnancy with an increase in cardiac output, plasma volume, heart rate, and creatinine clearance, and a decrease in blood pressure and total peripheral vascular resistance. Women who developed a recurrent hypertensive disorder differed from their counterparts with an uneventful next pregnancy by smaller pregnancy-induced increases in creatinine clearance (19% vs. 31%, P = .035) and cardiac output (10% vs. 20%, P = .035), respectively. CONCLUSION: The initial systemic cardiovascular and renal adaptations to pregnancy in women who develop a recurrent gestational hypertensive disorder differ from those in their counterparts with an uneventful next pregnancy by smaller rises in creatinine clearance and cardiac output.

Early-pregnancy asymmetric dimethylarginine (ADMA) levels in women prone to develop recurrent hypertension.

OBJECTIVE: To evaluate early-pregnancy levels of ADMA (asymmetric dimethylarginine) in recurrent hypertensive pregnancy. STUDY DESIGN: In this retrospective observational study, blood samples from 35 normotensive women with a previous hypertensive pregnancy were obtained preconceptionally and at 12, 16 and 20weeks in their next pregnancy. We assessed ADMA, symmetric dimethylarginine (SDMA), l-arginine and l-citrulline. We analyzed differences in longitudinal patterns between normotensive (NT, n=18) and recurrent hypertensive (HT, n=17) pregnancies by linear mixed models, with a sub-analysis for preeclampsia (PE, n=6). MAIN OUTCOME MEASURES: ADMA, SDMA, l-arginine and l-citrulline. RESULTS: Pre-pregnant SDMA and l-citrulline were lower in HT. At 12weeks, ADMA and ADMA/SDMA ratio correlated inversely with PAPP-A and ß-hCG, respectively. In both groups, ADMA-related compounds changed inconsistently with advancing (mid-trimester) pregnancy, although in HT, l-arginine tended to decrease between 16 and 20weeks, a decline consistent in PE. CONCLUSION: These data support a modest role for ADMA and related metabolites in the pathogenesis of hypertensive pregnancy.

PP036. Cardiovascular disease risk factors among women with a history of placental abruption.

INTRODUCTION: Several studies have shown that the risk of premature cardiovascular disease (CVD) is increased after maternal placental syndromes (MPS), including hypertensive disorders and placental abruption. Although a high prevalence of CVD risk factors has been observed for women with a history of preeclampsia and pregnancy-induced hypertension, it is unclear whether patients with previous placental abruption exhibit the same cardiovascular risk profile. OBJECTIVES: To investigate the association of placental abruption with the presence of modifiable CVD risk factors that may be of potential use for prevention programs. METHODS: We performed a case-control study of 75 women with a history of placental abruption and a control group of 79 women with uneventful pregnancies. At 6-9months postpartum we measured the following CVD risk factors: blood pressure, body-mass index (BMI), fasting blood glucose levels, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and CRP. Baseline variables in the two groups with and without a previous abruption were expressed as means and standard deviations (SD). Where appropriate, means were adjusted for potential confounders using a generalized linear model. Data were further stratified for women with or without additional MPS-related complications, i.e. preeclampsia, gestational hypertension and intrauterine growth restriction. RESULTS: Women who experienced placental abruption had a significantly higher systolic and diastolic blood pressures, BMI, fasting blood glucose levels, CRP, total cholesterol, HDL-cholesterol, LDL-cholesterol and cholesterol/HDL ratio, as compared to controls. These associations remained significant in women with previous placental abruption without concomitant other MPS only for plasma lipid profile, BMI and fasting blood glucose levels, but not for diastolic and systolic blood pressure. CONCLUSION: A history of placental abruption is independently associated with increased BMI, fasting blood glucose levels, total cholesterol and LDL-cholesterol postpartum. Early detection of CVD risk factors in women with previous placental abruption offers an attractive opportunity for primary and secondary prevention.

Role of protein S and tissue factor pathway inhibitor in the development of activated protein C resistance early in pregnancy in women with a history of preeclampsia.

Pregnancy increases the risk of venous thromboembolism. Particularly in early pregnancy, the thrombosis risk can be attributed to the changes in coagulation. Elevated thrombin generation and resistance to activated protein C (APC) are likely to contribute to the increased thrombosis risk during pregnancy. We studied changes and the determinants of thrombin generation and APC resistance in the first 16 weeks of gestation in women with history of preeclampsia. Additionally, we investigated the influence of pregnancy-induced haemodilution on the coagulation system. We measured thrombin generation, APC resistance and plasma levels of prothrombin, factor V, factor X, protein S and tissue factor pathway inhibitor (TFPI) in 30 non-pregnant and 21 pregnant women at 8, 12 and 16 weeks of gestation. All participants shared a history of a hypertensive complication in the preceding pregnancy. Thrombin generation and APC resistance were higher at eight weeks of pregnancy than in the non-pregnant state, and progressively increased between eight and 16 weeks of gestation. Changes in the TFPI and protein S levels accounted for ~70% of pregnancy-induced APC resistance. Interestingly, a significant correlation (slope 2.23; 95%CI: 1.56 to 2.91; r= 0.58) was observed between protein Stotal or protein Sfree levels and haematocrit. In conclusion, pregnancy induces a decrease of TFPIfree and protein Sfree levels that attenuates the function of the TFPI and protein C systems and results in elevated thrombin generation and increased APC resistance. Besides, our data suggest that pregnancy-dependent haemodilution may contribute to the decreased peripheral protein S levels.

Early-pregnancy changes in cardiac diastolic function in women with recurrent pre-eclampsia and in previously pre-eclamptic women without recurrent disease.

OBJECTIVE: To compare early-pregnancy changes in cardiac diastolic function between formerly pre-eclamptic women with (RECUR) and without (NORECUR) recurrent pre-eclampsia. DESIGN: Retrospective observational cohort study. SETTING: Tertiary referral centre. POPULATION: Pregnant women with a history of early-onset pre-eclampsia (n = 34). METHODS: The peak mitral filling velocity in early diastole (E) and at atrial contraction (A), and the E/A ratio were assessed before and at 12, 16 and 20 weeks of gestation in the next pregnancy. Differences in early-pregnancy alterations between women with (RECUR) and without (NORECUR) recurrent pre-eclampsia were evaluated by use of mixed design analysis of covariance. MAIN OUTCOME MEASURES: Cardiac function and recurrent pre-eclampsia. RESULTS: In ten women (29%) pre-eclampsia recurred. By 12 weeks of gestation the E/A ratio had increased in the RECUR group, but not in the NORECUR group (P < 0.01). Moreover, from 16 weeks of gestation onwards, the RECUR group had a lower cardiac output and higher systemic vascular resistance as compared with the NORECUR group (P < 0.05). CONCLUSION: Our results suggest that formerly pre-eclamptic women destined to develop recurrent pre-eclampsia differ from their counterparts who do not develop recurrent pre-eclampsia by impaired first-trimester adaptation of cardiac diastolic function.

The visually-evoked cerebral blood flow response in women with a recent history of preeclampsia and/or eclampsia.

Several studies provide evidence for altered cerebral hemodynamics during (pre)eclampsia. Whether (pre)eclampsia has a persistent negative impact on cerebral hemodynamics, possibly contributing to an elevated risk of premature stroke, is unknown. The aims of this study were (i) to refine and apply a control system-based method previously introduced by Rosengarten to quantify the visually-evoked blood flow response of the posterior cerebral artery (PCA); and (ii) to test the hypothesis with this method that cerebral hemodynamics in women with a recent history of (pre)eclampsia is abnormal relative to that in parous controls. Hereto, we recorded cerebral blood flow velocity (CBFV) in the PCA by transcranial Doppler (TCD) sonography during cyclic visual stimulation in 15 former preeclamptics, 13 former eclamptics and 13 controls. The typical CBFV response was fitted with the step response of a second-order-linear model enabling quantification by parameters K (gain), zeta (damping), omega (natural frequency), T(v) (rate time) and T(d) (time delay). The method refinement introduced here consisted of response filtering before quantification and of considering the individual instead of group-averaged response patterns. Application of this refinement reduced the fitting errors (1.4 +/- 1.2 vs. 3.2 +/- 1.8, p < 0.01). Intergroup differences in model parameters were not found. Although statistically not significant, a trend was observed that critical damping (zeta>1) occurred more frequently in the combined group of former patients than in the controls (7 of 28 vs.1 of 13, p = 0.16). Critical damping (zeta>1) reflects an abnormal response, which is either compensated for by a rise in rate time ("intermediate"; zeta>1; T(v) > 20) or remains uncompensated ("sluggish"; zeta>1; T(v) < 20). Critical damping increased significantly (p = 0.039) with (pre-)eclampsia-to-test-interval in the PE+E patients with abnormal responses (zeta>1), suggesting that (pre)eclampsia might induce diminishing cerebral hemodynamic function over time. Based on a system-analytical classification approach, the data of this study provide evidence for individual CBFV responses to be abnormal in former (pre)eclamptics compared with controls. Further study is needed to reveal how the abnormal CBFV response classification reflects cerebrovascular dysfunction.

Mechanisms leading to increased vasodilator responses to calcitonin-gene-related peptide in mesenteric resistance arteries of early pregnant rats.

The objective of this study was to explore the mechanism responsible for the higher relaxing responses of mesenteric arteries to calcitonin-gene-related peptide (CGRP) in pregnancy. We performed myograph and ligand binding studies to determine the role of matrix metalloproteinase-2 (MMP-2) and CGRP receptor density. MMP activity was manipulated in isolated arteries by exposing them to the blocking effects of doxycycline. Vascular activity of MMP-2 was studied by gelatin zymography, and CGRP receptor density was determined by ligand binding analysis. Compared to nonpregnant rats, CGRP elicited stronger arterial relaxation in pregnant rats. The latter effect was neither accompanied by a change in relaxing responses to direct activation of adenylyl cyclase by forskolin nor by a change in the response to stimulation of G-protein-coupled adrenergic receptors by isoproterenol. Doxycycline did not affect the stronger arterial relaxation in pregnancy in spite of the observed more than threefold higher arterial MMP-2 activity. Density of binding sites for [(125)I]CGRP in arteries from pregnant rats (64 +/- 14 fmol/mg protein) and from virgin rats (54 +/- 5 fmol/mg protein) were comparable. The results of this study provide evidence for increased coupling of CGRP receptors to adenylyl cyclase in early pregnancy.

Pregnancy enhances the prejunctional vasodilator response to adrenomedullin in selective regions of the arterial bed of Wistar rats.

The objective of this study is to determine whether the vascular response to adrenomedullin is modulated by pregnancy. To this end, the authors study the effect of adrenomedullin on different contractile responses of mesenteric, uterine, renal, and saphenous arteries of 10-day pregnant and nonpregnant rats in myographs. Adrenomedullin inhibited contractile responses induced by electrical field stimulation in only the mesenteric and uterine arteries. This effect was more pronounced during pregnancy than in the nonpregnant state. Adrenomedullin did not modify concentration response curves to noradrenaline. The reduction of contractile responses to 40 mmol/L K(+) by adrenomedullin was similar in arteries of pregnant and nonpregnant rats. However, after incubation with capsaicin, this effect was significantly increased in mesenteric arteries of the pregnant group. The authors conclude that pregnancy is associated with a rise in the prejunctional inhibitory effect of adrenomedullin in some regions of the arterial system.

Vasodilator reactivity to calcitonin gene-related peptide is increased in mesenteric arteries of rats during early pregnancy.

The objective of the present study was to determine the effect of early pregnancy on the sensitivity to, and endogenous production of calcitonin gene-related peptide (CGRP). Contractile responses of arteries of 10-day pregnant and nonpregnant rats were studied in myographs. During contractions induced by 40 mmol/l K(+), exogenous CGRP elicited an approximately 30% stronger relaxation in mesenteric arteries in pregnancy, an effect not seen in renal and uterine arteries. Capsaicin treatment during K(+)-induced contractions caused a persistent potentiation of the contractile response in mesenteric arteries, indicating that K(+) stimulates the endogenous release of CGRP. This potentiation was similar in the pregnant and nonpregnant state (+81 +/- 23% and +82 +/- 23%, respectively), suggesting no effect of pregnancy on the endogenous CGRP release. The latter was paralleled by comparable CGRP content in the arteries of both groups, indicating similar tissue CGRP availability. The results of this study support the concept that early pregnancy is associated with a rise in the vascular sensitivity to CGRP in selected areas of the vascular bed without concomitant increase in the vascular CGRP production and release.