Pregnancy-induced atypical haemolytic uremic syndrome : a new era with Eculizumab

Pregnancy is a well-recognised trigger of atypical haemolytic syndrome (P-aHUS) and often occurs in the post-partum period. Similar to atypical haemolytic uremic syndrome, it carries a poor prognosis with high morbidity particularly in the form of renal failure. Early recognition and intervention is crucial in its management particularly with the recent availability of Eculizumab, a humanized monoclonal antibody to complement component C5, which has demonstrated drastic improvement in prognosis. The issue, however, is arriving at a timely diagnosis given the considerable amount of overlap in the clinical and biochemical manifestation of P-aHUS, HELLP syndrome (haemolysis, elevated liver enzyme and low platelet count) and other hypertensive disorders of pregnancy. We present a case report and literature review that highlights the clinical conundrum of arriving at the diagnosis. We also highlight the importance of early management of P-aHUS with Eculizumab and its impact on improving morbidity

Aspirin in the prevention of preeclampsia : the conundrum of how, who and when

Aspirin is widely used in preventing early onset preeclampsia in women who are identified as being high risk. Although the benefit of aspirin is increasingly evident and acknowledged, there remains many unanswered questions with regards to its optimal application in pregnancy. The issues mainly centre around the relatively modest risk reduction that is observed with the use of aspirin prophylactically. We aim to explore the reasons behind the conservative rate of benefit and aim to explore factors that are likely to influence the outcomes with the use of aspirin

Assessment and management of primary aldosteronism in pregnancy : a case-control study

Context: Primary aldosteronism (PA) is a common secondary cause of hypertension. Literature regarding PA in pregnancy has demonstrated poor outcomes. Objective: Compare the management and outcomes of PA in pregnancy to both high and low-risk matched controls. Methods: This was a case-control trial conducted in a network of metropolitan hospitals in Sydney, Australia. PA women (positive salt suppression test) with singleton pregnancies delivered after 20 weeks' gestation were matched to women with high- and low-risk pregnancies. Management outcomes included pre-eclampsia prophylaxis and antihypertensive medications required prenatally, antenatally, and postnatally. Maternal outcomes included incidence of pre-eclampsia, gestational diabetes, hypokalemia, mode of delivery, and length of stay postpartum. Neonatal outcomes included gestation, birthweight, intensive care unit admission, and length of stay. Results: Fifty-nine women with 60 pregnancies were included (20 PA, 20 high risk, and 20 low risk). The number of antihypertensive medications women with PA took prepregnancy was similar to the high-risk group. A similar proportion of women in the PA and high-risk groups were prescribed pre-eclampsia prophylaxis and developed pre-eclampsia. Even after adjustment for several factors, PA was not independently associated with pre-eclampsia development. Women with PA had higher antihypertensive requirements and a longer stay in hospital postpartum than the high-risk group (both P = .02). There was no difference in neonatal adverse outcomes. Four women took epleronone during pregnancy without any adverse effects noted. Conclusion: Women with PA required more antihypertensives and had a longer postpartum length of stay than matched high-risk women, but similar rates of pre-eclampsia. There was no difference in the rate of neonatal intensive care admissions or adverse outcomes for neonates

Galectin-1-related modulation of trophoblast endothelial interactions by integrins α1 and β1

During normal trophoblast invasion, integrins α6β4 are downregulated, and α1β1 are upregulated in invasive cytotrophoblast cells. In preeclampsia both interstitial and endovascular invasion are shallow and cytotrophoblasts fail to upregulate α1β1 and downregulate α6β4. This study aims to investigate the role of integrins α1β1 and α6β4 on cellular pathways influencing trophoblast integration into endothelial cellular networks in vitro. Red fluorescent-labeled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on Matrigel to form endothelial networks. Green fluorescent-labeled trophoblastic HTR-8/SVneo cells pre-incubated with 20 μg/ml of neutralizing antibodies (anti-α1, β1, α6, β4, α1 + β1, or α6 + β4) for 1 h were then co-cultured with endothelial networks with the neutralizing antibodies for 24 h. Fluorescent images were captured, and quantified utilizing Image J. Cells were retrieved to analyze mRNA expression of galectin-1, TIMP-1, and PAI-1 by quantitative PCR. MMP-2, MMP-9, free sFlt-1, and PlGF from conditioned media were measured by ELISA. The integration of trophoblast cells into endothelial cellular networks was inhibited by anti-β1(− 28 ± 3%, p < 0.0001), and increased by anti-α6(+ 19 ± 5%, p < 0.01). Galectin-1 mRNA expression was decreased by anti-α1(− 35 ± 7%, p < 0.001), anti-β1(− 23 ± 5%, p < 0.05), and anti-α1+β1(− 35 ± 5%, p < 0.001). The mRNA expression of TIMP-1 was inhibited by anti-α1(− 59 ± 9%, p < 0.01) and anti-β1(− 63 ± 7%, p < 0.001) while PAI-1 mRNA expression was increased by anti-α1 + β1(+ 285 ± 70%, p < 0.0001). In the conditioned medium, anti-α1 reduced MMP-2(−28 ± 1%, p < 0.001), MMP-9(−27 ± 8%, p < 0.01), and sFlt-1(−27 ± 5%, p < 0.001) production. Anti-β1 reduced MMP-2(− 15 ± 2%, p < 0.05) production. There were no changes in PlGF. Appropriate integrins α1β1 modulate trophoblast cell integration into endothelial cellular networks in vitro through invasive pathways including galectin-1, TIMP-1, PAI-1, MMP-2, and MMP-9 production

The effect of acetyl salicylic acid (Aspirin) on trophoblast-endothelial interaction in vitro

Early administration of low dose acetyl salicylic acid (Aspirin) in high risk women reduces the risk of early onset preeclampsia. This study aims to investigate the effect of aspirin on trophoblast integration and the its effect on angiogenic and invasive pathways in an in-vitro model of preeclampsia. Red fluorescent-labeled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on matrigel to form endothelial networks. Green fluorescent-labeled trophoblastic HTR-8/SVneo cells were co-cultured with the endothelial networks with/without TNF-a (0.5 ng/mL) and/or aspirin (0.1 mM) for 24 h. Fluorescent images were captured and quantified by Image J to examine the effects of TNF-a and aspirin on the trophoblast-endothelial integration. Conditioned media were collected to measure free VEGF, PlGF and sFlt-1 by ELISA and PGF1a by Enzyme immunoassay (EIA). Cells were retrieved to examine mRNA expression of angiogenic factors (VEGF, PlGF and sFlt-1), invasion markers (MMP-2 and TIMP-1), endothelial cell activation markers (E-selectin and VCAM), eNOS and cyclooxygenase (COX)-2 by quantitative PCR. Aspirin reversed the inhibitory effect of TNF-a on trophoblast cell integration into endothelial cellular networks. TNF-a increased PGF1a production (128 +_ 11%, p < 0.05), whilst aspirin reversed the TNF-a effect on PGF1a production (19 +¬_ 4%, p < 0.01). TNF-a decreased the mRNA expression of PlGF, eNOS, MMP-2 and TIMP-1, and stimulated COX2, E-selectin and VCAM mRNA expression. Aspirin did not reverse the TNF-a effect on these molecules. Aspirin improves trophoblast cell integration into endothelial cellular networks by inhibiting the effect of TNF-a via PGI2 with no significant effect on antiangiogenic, invasive or endothelial activation markers

Clinical influence of nonadherence with prophylactic aspirin in preventing preeclampsia in high-risk pregnancies : a multicenter, prospective, observational cohort study

Aspirin nonadherence and its associated increase in cardiovascular and cerebrovascular events is well described; however, the prevalence of aspirin nonadherence among high-risk pregnant women at risk of preeclampsia and its influence on clinical outcomes remains unclear. Our study examined the prevalence of aspirin nonadherence and resistance among high-risk pregnant women quantitatively (platelet function analyzer 100 and plasma salicylic acid) and clinical outcomes relative to adherence. High-risk pregnant women were recruited across 3 centers in the South West Sydney Local Health District. Simultaneous clinic data, blood sample, and self-reported adherence assessment were prospectively collected at 4-week intervals from 12 to 36 weeks of gestation. Nonadherence was defined as normal platelet function analyzer 100 and nondetectable plasma salicylic acid in <90% of time points. Value of <90% is based on current data. Two hundred twenty women were recruited over 25 months. No woman was aspirin resistant, and 63 (44%) women demonstrated inadequate adherence. Women with inadequate adherence had higher incidence of early-onset preeclampsia (17% versus 2%; odds ratio [OR], 1.9 [95% CI, 1.1–8.7]; P=0.04), late-onset preeclampsia (41% versus 5%; OR, 4.2 [95% CI, 1.4–19.8]; P=0.04), intrauterine growth restriction (29% versus 5%; OR, 5.8; [95% CI, 1.2–8.3]; P=0.001), preterm delivery (27% versus 10%; OR, 5.2 [95% CI, 1.5–8.7]; P=0.008), and higher likelihood of increase in antihypertensives antenatally (60% versus 10%; OR, 4.6 [95% CI, 1.2–10.5]; P=0.003). Kaplan-Meier analysis demonstrated lower incidence of premature delivery in the ≥90% adherent group (HR, 0.3 [95% CI, 0.2–0.5]; P<0.001).Kappa coefficient agreement between qualitative and quantitative assessment of adherence was moderate (κ=0.48; SE=0.029; P<0.0001). Our data demonstrates that aspirin is an effective prophylactic agent with an absolute risk reduction of 51% (number needed to treat, 2) when adherence is ≥90%, compared with women with inadequate adherence. Women who were <90% adherent had higher rates of preeclampsia, intrauterine growth restriction, preterm delivery, and increase in antenatal antihypertensive requirements. Self-reported adherence does not accurately reflect actual adherence

Vertebral artery dissection in hypertensive disorders of pregnancy : a case series and literature review

Background: Arterial dissection is a rare complication of pregnancy and puerperium. There have been reports of aortic, coronary and cervical artery dissection in association with preeclampsia, however, vertebral artery dissection is rarely reported particularly in the antenatal setting in the presence of a Hypertensive Disorder of Pregnancy (HDP).The general annual incidence of symptomatic spontaneous cervicocephalic arterial dissection is 0.0026 % and a data registry reported that 2.4 % of these occurred in the post-partum period. The actual incidence of vertebral artery dissection in HDP is unknown as the current literature consists of case series and reports only with most documenting adverse outcomes. Given the presence of collateral circulation, unilateral vertebral artery dissections may go unrecognised and may be more common than suspected. Case presentation: We present a case series of four patients with vertebral artery dissection in association with HDP, two of which occurred in the antenatal setting and two in the post-partum setting. All our patients had favourable outcome with no maternal neurological deficit and live infants. Our discussion covers the proposed pathophysiology of vertebral artery dissection in HDP and the management of it. Conclusion: Our case series highlights the need to consider VAD an important differential diagnosis when assessing pregnant women with headache and neck pain particularly in the context of HDP

The 15-epilipoxin-A4 pathway (ATL) with prophylactic aspirin in preventing preeclampsia : a longitudinal-cohort study

Introduction: The benefit of aspirin in preventing preeclampsia is increasingly recognised, however, its mechanism of action remains unclear. Non-obstetric studies have described an anti-inflammatory effect of aspirin through 15-epilipoxin-A4(ATL). However, the anti-inflammatory mechanism of aspirin in the prevention of preeclampsia remains unknown. Objective/Hypothesis: To examine the (1) difference in longitudinal endogenous lipoxin-A4(EnLipoxin-A4) concentration in low-risk(LR) and high-risk(HR) pregnancies, (2)effect of aspirin on endogenous ATL concentration and the associated effect on cytokine profile of HR women. Methods: Plasma from 220 HR women were collected at 12,16,20,24,28,32 and 36 weeks of gestation. Adherence to aspirin was biochemically verified. Plasma En-Lipoxin-A4 and ATL concentrations were analysed through liquid-chromatography mass-spectrometry(LC-MS/MS) and cytokines;IL-10, TNF-α, IFN-ɣ, IL-8 and IL-1β with high-sensitivity multi-bead Luminex® assay. Results: HR women have up to 70% lower plasma concentration of En-Lipoxin-A4(p<0.001) compared to LR women. HR women with adequate aspirin adherence(HR-AA)(n=82) had higher plasma concentration of ATL(p<0.001), lower concentration of IL-8 from 16-36 weeks of gestation(p<0.001) )and increased IL-10 concentration from 16 – 28 weeks of gestation (p=0.03) in comparison to high-risk women who were not on aspirin(HR-NA). HR-AA who did not develop preeclampsia had higher plasma En-lipoxin-A4(p<0.0001), ATL(p=0.02) and IL-10 concentrations(p<0.001) with lower IL-8 concentration(p=0.004) compared to HR who developed preeclampsia. Discussion: Plasma concentration of En-Lipoxin-A4 is lower in HR women compared to LR controls. Adequate adherence with aspirin results in an increase in ATL and IL-10 with reduced IL-8 plasma concentration. This study suggests a potential anti-inflammatory role of aspirin, through the ATL pathway with prophylactic aspirin in HR pregnant women

The utility of sonographic assessment in selecting patients for percutaneous insertion of peritoneal dialysis catheter

Background: Percutaneous insertion of peritoneal dialysis (PD) catheters by nephrologists is a safe and effective alternative to open surgical techniques. These patients are usually carefully selected due to anatomical considerations and medical comorbidities, with the current literature suggesting exclusion of patients with prior abdominal surgery.Method: We conducted a retrospective cohort study of predialysis patients who attended a preprocedural clinic in a tertiary center over 6 years. Procedural complications and catheter survival were assessed. Chi-squared test and Kaplan-Meier survival analysis were undertaken. Inpatient assessments were excluded.Results: A total of 217 patients were assessed, of whom 171 (78.8%) were accepted for percutaneous PD catheter insertion by a nephrologist. The key exclusion criteria were: (1) the clinical presence of abdominal hernia (p 5.5 cm (p < 0.001) and (3) ultrasound findings of impaired visceral slide test (p < 0.001). Prior abdominal surgery was not a default exclusion criterion (p = 0.1), as 63 patients (37%) with prior abdominal surgery, average of 1.3 prior surgeries per patient, were assessed as appropriate for the percutaneous procedure. There was no difference in the procedural complication rate and catheter survival between patients with and without prior abdominal surgery.Conclusion: A comprehensive preprocedural assessment utilizing ultrasound permits an objective selection of patients for percutaneous insertion of PD catheters by nephrologists. This allowed for successful and safe percutaneous insertion of PD catheters in patients who may have otherwise been excluded, e.g., prior abdominal surgery, patients with large bilateral polycystic kidneys, and central obesity

A pharmacokinetic assessment of optimal dosing, preparation and chronotherapy of aspirin in pregnancy

Background: The benefit of aspirin in preventing preeclampsia is well established, however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing and preparation of aspirin Objective(s): We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid (SA), in pregnant women to non-pregnant women and examine the effect of dose (100mg vs 150mg), preparation (enteric coated (EC) vs non-EC) and chronotherapy of aspirin (morning vs night) between both groups. Study design: Twelve high-risk pregnant women and three non-pregnant women were enrolled into this study. Pregnant women were in one of four groups (100mg EC, 100mg non-EC, 150mg non-EC morning dosing and 150mg non-EC night dosing) whilst non-pregnant women undertook each of the four dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (pre-ingestion), 1, 2, 4, 6, 12 and 24-hours post-ingestion of aspirin. Plasma obtained was analysed for SA levels through liquid chromatography mass spectrometry (LCMS). Pharmacokinetic values of area under the curve (AUC(t-24)), point of maximum concentration (Cmax), time of maximum concentration (Tmax), volume of distribution (Vd), clearance (CL) and elimination half-life (t½) were analysed for statistical significance with SPSSv25 Results: Pregnant women had a 40% ± 4% reduction in AUC(t-24) (p <0.01) and 29% ± 3% reduction in Cmax (p<0.01) with a 44% ± 8% increase in CL (p<0.01) in comparison to non-pregnant women when 100 mg of aspirin was administered. The reduction in AUC(t-24), however, was minimized with the use of 150mg of aspirin in pregnant women, with which, the AUC(t-24) was closer to that achieved with the use of 100mg aspirin in non-pregnant women. There was a 4-hour delay (p<0.01) in the Tmax, 47% ± 3% reduction in Cmax (p<0.01) and a 48% ± 1% increase in Vd (p<0.01) with the use of 100mg EC aspirin compared to non-EC aspirin with no difference in the overall AUC. There was no difference in the pharmacokinetics of aspirin between morning and night dosing. Conclusion(s): There is a reduction in the total drug metabolite concentration of aspirin in pregnancy and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric coated and non-enteric coated aspirin and between morning and night dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings