Nina D. Paauw

Long-term renal and cardiovascular risk after preeclampsia: towards screening and prevention.

Preeclampsia (PE) is a hypertensive pregnancy disorder complicating up to 1-5% of pregnancies, and a major cause of maternal and fetal morbidity and mortality. In recent years, observational studies have consistently shown that PE carries an increased risk for the mother to develop cardiovascular and renal disease later in life. Women with a history of PE experience a 2-fold increased risk of long-term cardiovascular disease (CVD) and an approximate 5-12-fold increased risk of end-stage renal disease (ESRD). Recognition of PE as a risk factor for renal disease and CVD allows identification of a young population of women at high risk of developing of cardiovascular and renal disease. For this reason, current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, these recommendations are based on low levels of evidence due to a lack of studies on screening and prevention in formerly preeclamptic women. This review lists the incidence of premature CVD and ESRD observed after PE and outlines observed abnormalities that might contribute to the increased CVD risk with a focus on kidney-related disturbances. We discuss gaps in current knowledge to guide optimal screening and prevention strategies. We emphasize the need for research on mechanisms of late disease manifestations, and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women.

Sildenafil During Pregnancy: A Preclinical Meta-Analysis on Fetal Growth and Maternal Blood Pressure.

Sildenafil is a new approach to treat fetal growth restriction (FGR) and preeclampsia. We performed a systematic meta-analysis to evaluate effects of sildenafil. Our search identified 22 animal studies (mouse, rat, rabbit, sheep, and guinea pigs) and 2 human randomized controlled trials. Data were pooled using ratio of means and mean differences with 95% confidence intervals for fetal growth and maternal blood pressure, respectively. Meta-regression analyses were performed for study-related factors that might affect efficacy of sildenafil, including the model used (healthy pregnancy versus FGR/preeclampsia) and route of administration. Dose–response curves with dose per metabolic weight (mg/kg0.75 per 24 hours) were fitted using splines. Our analyses show that sildenafil increases fetal growth during FGR/preeclampsia pregnancy compared with healthy pregnancy (1.10 [1.06–1.13] versus 1.03 [0.99–1.06]; P=0.006). There was no significant effect on fetal growth in the absence of FGR/preeclampsia. Effects were similar among different species and largest after oral and continuous administration. There was a positive relation between dose and fetal growth up to a human equivalent dose of ≈450 mg/d. A significant blood pressure–lowering effect of sildenafil is present during FGR/preeclampsia pregnancy only (−19 [−25 to −13] mm Hg; P<0.01), with the effect size being highly dependent on baseline blood pressure and without effect in the absence of hypertension. This meta-analysis supports that sildenafil improves fetal growth and maternal blood pressure regulation during FGR and preeclampsia pregnancy. The greatest beneficial effects on fetal growth are with dosages greater than those currently used in human studies.

High-Normal Estimated Glomerular Filtration Rate in Early-Onset Preeclamptic Women 10 Years Postpartum

Women with a history of preeclampsia have a 5- to 12-fold increased risk to develop end-stage kidney disease. Previous observations in small cohorts suggest that former preeclamptic (fPE) women have subtle abnormalities in renal hemodynamics and renal function, which might predispose them to renal failure in later life. In this study, we analyzed renal function in a cross-sectional cohort consisting of former early-onset preeclamptic (fPE, n=339) and former healthy pregnant women (fHP, n=332), overall with a mean age of 39 years at 10 years postpartum. Estimated glomerular filtration rate (eGFR), assessed by the modification of diet in renal disease (MDRD) and chronic kidney disease–epidemiology (CKD-epi) equations, and urinary protein:creatinine ratios were assessed 10 years postpartum. Median MDRD and CKD-epi eGFR did not significantly differ between fHP and fPE groups, whereas a comparison of distribution of eGFR revealed a shift toward a high-normal MDRD eGFR in the fPE group (&khgr;2, P=0.02) with the same trend for CKD-epi eGFR (&khgr;2, P=0.18). The odds ratio for fPE women having MDRD eGFR >110 mL/min per 1.73 m2 was 1.6 (1.1–2.4). In addition, the median urinary protein:creatinine ratio was slightly higher in fPE (8.5 versus 7.1 mg/mmol; P<0.01) and correlated positively with both MDRD and CKD-epi eGFR in fPE women. No increased incidence of CKD in fPE women was observed. In conclusion, we demonstrate subtle changes in renal function in former early-onset preeclamptic women 10 years postpartum, characterized by a high-normal eGFR and a slightly higher protein excretion. Whether these subtle differences predispose to or predict long-term renal function loss in fPE women remains to be investigated. Clinical Trial Registration—URL: http://www.trialregister.nl. Unique identifier: NTR2668.

Impaired sodium-dependent adaptation of arterial stiffness in formerly preeclamptic women: the RETAP-vascular study

Women with a history of preeclampsia have an increased risk for cardiovascular diseases later in life. Persistent vascular alterations in the postpartum period might contribute to this increased risk. The current study assessed arterial stiffness under low sodium (LS) and high sodium (HS) conditions in a well-characterized group of formerly early-onset preeclamptic (fPE) women and formerly pregnant (fHP) women. Eighteen fHP and 18 fPE women were studied at an average of 5 yr after pregnancy on 1 wk of LS (50 mmol Na(+)/day) and 1 wk of HS (200 mmol Na(+)/day) intake. Arterial stiffness was measured by pulse-wave analysis (aortic augmentation index, AIx) and carotid-femoral pulse-wave velocity (PWV). Circulating markers of the renin-angiotensin aldosterone system (RAAS), extracellular volume (ECV), nitric oxide (NO), and hydrogen sulfide (H2S) were measured in an effort to identify potential mechanistic elements underlying adaptation of arterial stiffness. AIx was significantly lower in fHP women on LS compared with HS while no difference in AIx was apparent in fPE women. PWV remained unchanged upon different sodium loads in either group. Comparable sodium-dependent changes in RAAS, ECV, and NO/H2S were observed in fHP and fPE women. fPE women have an impaired ability to adapt their arterial stiffness in response to changes in sodium intake, independently of blood pressure, RAAS, ECV, and NO/H2S status. The pathways involved in impaired adaptation of arterial stiffness, and its possible contribution to the increased long-term risk for cardiovascular diseases in fPE women, remain to be investigated.

Elevated renal tissue oxygenation in premature fetal growth restricted neonates: An observational study

Background Fetal growth restriction (FGR) is associated with an increased risk for kidney disease in later life. Studies reporting on early signs of renal disturbances in FGR are sparse and mostly include invasive measurements, which limit the possibility for early identification and prevention. We aim to investigate whether renal tissue oxygen saturation (rSO2) measured with near-infrared spectroscopy (NIRS) and the derived value fractional tissue oxygen extraction (FTOE) differ between premature FGR and control neonates in the first three days after birth. Methods Nine FGR and seven control neonates born <32 weeks of gestation were included. FGR was defined as biometry <p10 combined with prenatal signs of placental insufficiency. Renal rSO2 was measured continuously with NIRS for 72 hours. FTOE was calculated as: (arterial saturation-rSO2)/arterial saturation. Renal artery blood flow (pulsatility and resistance index) was measured within 24 hours after birth. A linear mixed model approach was used (intercept ± slope = r) to analyze the NIRS parameters. Results Renal rSO2 was higher in FGR neonates compared to controls (94% vs. 83%; pgroup = 0.002). During the first three days after birth, renal rSO2 decreased in FGR neonates and increased in controls (r = -0.25 vs. r = 0.03; pinteraction = 0.001). Renal FTOE was lower in FGR neonates (0.02 vs. 0.14; pgroup = 0.01) and increased slightly during three days after birth, while it remained stable in controls (r = 0.003 vs. r = -0.0001; pinteraction = 0.001). Renal artery blood flow was similar between groups. Conclusions FGR neonate kidneys showed higher rSO2 as measured with NIRS and lower derived values of FTOE in the first three days after birth. We speculate that this was caused by either a reduced oxygen consumption due to impaired renal maturation or increased renal oxygen supply. How these observations correlate with short- and long-term renal function needs further investigation before renal NIRS can be implemented in screening and prevention in clinical practice.

Cardiovascular Sequels During and After Preeclampsia

Preeclampsia is a pregnancy-specific disorder complicating 2%-8% of pregnancies worldwide and characterized by de novo development of hypertension and proteinuria. Current understanding of the pathophysiology of preeclampsia is limited. A main feature is disrupted spiral artery remodeling in the placenta, which restricts the blood flow to the placenta, which in turn leads to decreased uteroplacental perfusion. Impaired blood flow through the placenta might result in fetal growth restriction and secretion of several factors by the placenta-mainly pro-inflammatory cytokines and anti-angiogenic factors-which spread into the maternal circulation, leading to endothelial dysfunction, which subsequently results in disrupted maternal hemodynamics. To date, no treatment options are available apart from termination of pregnancy. Despite normalization of the maternal vascular disturbances after birth, it has become apparent that formerly preeclamptic women experience an increased risk to develop cardiovascular and kidney disease later in life. One well-accepted concept is that the development of preeclampsia is an indicator of maternal susceptibility to develop future cardiovascular conditions, although the increased risk might also be the result of organ damage caused during preeclampsia. Given the associations between preeclampsia and long-term complications, preeclampsia is acknowledged as woman-specific risk factor for cardiovascular disease. Current research focuses on finding effective screening and prevention strategies for the reduction of cardiovascular disease in women with a history of preeclampsia.

Postpartum increases in cerebral edema and inflammation in response to placental ischemia during pregnancy

Reduced placental blood flow results in placental ischemia, an initiating event in the pathophysiology of preeclampsia, a hypertensive pregnancy disorder. While studies show increased mortality risk from Alzheimers disease, stroke, and cerebrovascular complications in women with a history of preeclampsia, the underlying mechanisms are unknown. During pregnancy, placental ischemia, induced by reducing uterine perfusion pressure (RUPP), leads to cerebral edema and increased blood-brain barrier (BBB) permeability; however whether these complications persist after delivery is not known. Therefore, we tested the hypothesis that placental ischemia contributes to postpartum cerebral edema and neuroinflammation. On gestational day 14, time-pregnant Sprague Dawley rats underwent Sham (n = 10) or RUPP (n = 9) surgery and brain tissue collected 2 months post-delivery. Water content increased in posterior cortex but not hippocampus, striatum, or anterior cerebrum following RUPP. Using a rat cytokine multi-plex kit, posterior cortical IL-17, IL-1α, IL-1β, Leptin, and MIP2 increased while hippocampal IL-4, IL-12(p70) and RANTES increased and IL-18 decreased following RUPP. Western blot analysis showed no changes in astrocyte marker, Glial Fibrillary Acidic Protein (GFAP); however, the microglia marker, ionized calcium binding adaptor molecule (Iba1) tended to increase in hippocampus of RUPP-exposed rats. Immunofluorescence staining revealed reduced number of posterior cortical microglia but increased activated (Type 4) microglia in RUPP. Astrocyte number increased in both regions but area covered by astrocytes increased only in posterior cortex following RUPP. BBB-associated proteins, Claudin-1, Aquaporin-4, and zonular occludens-1 expression were unaltered; however, posterior cortical occludin decreased. These results suggest that 2 months postpartum, neuroinflammation, along with decreased occludin expression, may partly explain posterior cortical edema in rats with history of placental ischemia.