Pamela Loughna

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

BACKGROUND Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Oxidative stress markers in hypertensive states of pregnancy: preterm and term disease

Discussion continues as to whether de novo hypertension in pregnancy with significant proteinuria (pre-eclampsia; PE) and non-proteinuric new hypertension (gestational hypertension; GH) are parts of the same disease spectrum or represent different conditions. Non-pregnant hypertension, pregnancy and PE are all associated with oxidative stress. We have established a 6 weeks postpartum clinic for women who experienced a hypertensive pregnancy. We hypothesized that PE and GH could be distinguished by markers of oxidative stress; thiobarbituric acid reactive substances (TBARS) and antioxidants (ferric ion reducing ability of plasma; FRAP). Since the severity of PE and GH is greater pre-term, we also compared pre-term and term disease. Fifty-eight women had term PE, 23 pre-term PE, 60 had term GH and 6 pre-term GH, 11 pre-existing (essential) hypertension (EH) without PE. Limited data were available from normotensive pregnancies (n = 7) and non-pregnant controls (n = 14). There were no differences in postpartum TBARS or FRAP between hypertensive states; TBARS (P = 0.001) and FRAP (P = 0.009) were lower in plasma of non-pregnant controls compared to recently-pregnant women. Interestingly FRAP was higher in preterm than term GH (P = 0.013). In PE and GH, TBARS correlated with low density lipoprotein (LDL)-cholesterol (P = 0.036); this association strengthened with inclusion of EH (P = 0.011). The 10 year Framingham index for cardiovascular risk was positively associated with TBARS (P = 0.003). Oxidative stress profiles do not differ between hypertensive states but appear to distinguish between recently-pregnant and non-pregnant states. This suggests that pregnancy may alter vascular integrity with changes remaining 6 weeks postpartum. LDL-cholesterol is a known determinant of oxidative stress in cardiovascular disease and we have shown this association to be present in hypertensive pregnancy further emphasizing that such a pregnancy may be revealing a pre-existing cardiovascular risk.

Smoking in pregnancy affects the fetal heart: possible links to future cardiovascular disease

Abstract Objectives: To investigate effects of maternal smoking on the fetal heart rate (FHR) in ambulatory patients using a portable fetal electrocardiogram recording device. Methods: A prospective cohort study of 43 pregnant smokers and 43 non-smoking gestation-matched controls with uncomplicated singleton pregnancies. Smokers were divided into light (1–10) and moderate (11–20 cigarettes/d). The FHR was recorded for 16 h with smokers smoking at will, using an event button to record when they lit a cigarette. Fifty recordings were made in the patients’ homes with 36 in ambulatory inpatients. Three consecutive 30-min epochs (before, during and after smoking) were compared with the controls. Results: Basal FHR was significantly lower before smoking in the foetuses of smokers compared with non-smokers (p = 0.048). During smoking, there was a significant dose-dependent fall in short-, long-term and true beat-to-beat variabilities (p = 0.004, p < 0.0001 and p = 0.024, respectively). Conclusion: Maternal smoking leads to reversible changes in FHR variability that mimic those associated with an increased incidence of adverse cardiovascular events in adults. As heart rate and variability reflect the autonomic control of the heart, our findings suggest that maternal smoking interferes with the autonomic control of the FHR.

Reduced placental vascular reactivity to 5-hydroxytryptamine in pre-eclampsia and the status of 5HT2A receptors

This study investigates the contractile response to 5 hydroxytryptamine (5HT) of chorionic artery and vein segments from normotensive (NT) and pre-eclamptic (PE) placentae. It also looked at the effectiveness of ketanserin (KET), a 5HT(2A) receptor antagonist, in reducing 5HT-mediated vasoconstriction. 5HT induced vasoconstriction in all of the vessels was studied. Compared to NT vessels, Emax (%KCl) was significantly reduced in PE arteries (p<0.05) and veins (p<0.0005). The mean Emax for NT arteries was 104.1 (±10.71) whilst PE arteries showed a mean Emax of 57.02 (±12.13). KET produced a statistically significant reduction of Emax in both vessels in NT and the arteries in PE. However the antagonistic effect of KET was not pronounced in PE veins. The EC50 values for NT and PE arteries and veins did not change significantly. There were no noticeable changes in the expression profiles of 5HT(2A) receptor mRNA and protein expressions. The data from this study suggest that in PE, the vascular reactivity of chorionic vessels to 5HT is reduced and it was not due to the altered expression of 5HT(2A) receptors.

OS102. Continuing pathology following a hypertensive pregnancy and the risk of future disease

INTRODUCTION New onset hypertension in pregnancy affects up to 6-8% of all pregnancies. For most women, hypertension and proteinuria settle following delivery. The National Institute for Health and Clinical Excellence (NICE) Hypertension in Pregnancy guideline recommends that this group of patients are reviewed by a medical professional postnatally [3]. However, studies have shown that blood pressure and urinalysis are often not checked in the postpartum period [4]. Women with a history of hypertension in pregnancy have a higher risk of future hypertension and cardiovascular disease (CVD) than women who have uncomplicated pregnancies [2]. Risk scores are available for assessing an individuals risk of CVD although they are not validated in women under 30. In UK, the most appropriate is QRISK2 score [1]. OBJECTIVES To determine the frequency of ongoing problems following a new onset hypertensive pregnancy and assess the risk of future cardiovascular disease. METHODS 351 women with new onset hypertension in pregnancy were reviewed 6 weeks postnatally. They were assessed for ongoing disease and cardiovascular risk. 10 year QRISK2 scores and heart age (the age at which a matched person has that score) were calculated. RESULTS 211 women with pre-eclampsia (PE) and 140 with gestational hypertension (GH) were reviewed. 9% and 11% of women with previous PE and GH respectively still required antihypertensive agents at follow-up. Only 1 woman required more than one antihypertensive medication (PE group). 19 women with PE (9%) had ongoing proteinuria (PCR>30). 5% had an estimated GFR <60ml/min. In addition to those with a strong family history of hypertension, 23 patients (6.5%) required investigation for ongoing problems. Risk factors for CVD were common 6 weeks after delivery: Although the overall risk of CVD was low (median 10 year QRISK2 score 0.3, median relative risk 1.0), with 41% of women having the lowest possible heart age, 22% of women had a significantly elevated risk of CVD (QRISK2 heart age ⩾age+10). CONCLUSION 16% of women had ongoing hypertension or proteinuria, evidence supporting the NICE guidance that all women with hypertension in pregnancy need follow-up after delivery. The overall risk of future CVD in women with previous hypertension in pregnancy is low but about one-fifth of women are at very high risk. A program of risk assessment is required to allow preventative measures to be implemented.

Postpartum evaluation of cardiovascular disease risk for women with pregnancies complicated by hypertension

OBJECTIVES Postpartum stratification of cardiovascular risk for women with pregnancies complicated by pre-eclampsia is challenging. Our aim was to identify potential clinical and biomarker predictors of future cardiovascular risk at six weeks postpartum in women with hypertensive pregnancies. STUDY DESIGN Prospective longitudinal cohort. MAIN OUTCOME MEASURES Ten year-Framingham cardiovascular risk scores were calculated for 477 women (94 with gestational hypertension, 288 with pre-eclampsia, 30 with superimposed pre-eclampsia, 51 with chronic hypertension, 14 women with uncomplicated pregnancies). B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL) and placental growth factor (PlGF) were quantified at six weeks postpartum. RESULTS Framingham cardiovascular risk scores were not higher in women with pregnancies complicated by pre-eclampsia than healthy controls, nor were scores higher in women with pre-existing chronic hypertension complicated with superimposed pre-eclampsia compared with those without superimposed pre-eclampsia. Women with gestational hypertension had higher risk scores than women with pre-eclampsia and healthy controls. Established risk factors of cardiovascular disease including diastolic blood pressure and previously diagnosed chronic hypertension were associated with higher scores, and African ethnicity, parity and estimated glomerular filtration rate also were independently associated with higher Framingham risk scores at six weeks postpartum. PlGF, BNP and NGAL concentrations were not associated with Framingham cardiovascular risk scores after adjustment for independent variables. CONCLUSIONS A history of pre-eclampsia or superimposed pre-eclampsia in most recent pregnancy was not associated with elevated Framingham risk score at six weeks postpartum. Established clinical predictors may enable risk stratification at six weeks postpartum, which are not enhanced by the biomarkers included in this study.

PP074. Persistent proteinuria after a pre-eclamptic pregnancy.

INTRODUCTION There is increasing evidence to suggest that both preeclampsia and microalbuminuria are linked to long term cardiovascular and renal disease [1,2]. OBJECTIVES To identify the proportion and characteristics of women with persistent significant proteinuria at 6 weeks following delivery. METHOD We examined the blood pressure, serum electrolytes and urine protein creatinine ratio (PCR) in a cohort of 219 women who were seen following a pre-eclamptic pregnancy in a postnatal clinic at a minimum of 6 weeks following delivery. RESULTS A PCR>50mg/mmol (considered to be clinically significant) was seen in 4.1% women at 6 weeks after delivery. Women with a higher antenatal PCR were more likely to have a PCR>50mg/mmol at 6 weeks postnatal (p=0.003). Antenatal or postnatal blood pressure was not correlated with persistent significant proteinuria. Neither estimated nor calculated glomerular filtration rate (eGFR) at 6 weeks correlated with those having persistent proteinuria, however there was a trend towards lower eGFR and higher serum creatinine antenatally in this group (p=0.138 and p=0.088). CONCLUSION There are a small but worrying number of women who still have clinically significant proteinuria at 6 weeks after a pre-eclamptic pregnancy. This represents a group of women who may have a higher risk of cardiovascular and renal disease.

PP075. Poor renal function following hypertensive pregnancy: Older mothers and smaller babies

INTRODUCTION There is increasing evidence that hypertensive pregnancy is a risk factor for renal disease [1]. OBJECTIVES To examine the correlation between maternal and offspring characteristics and impaired glomerular filtration rate following a hypertensive pregnancy. METHOD We calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula corrected for body surface area in a cohort of 422 women at 6 weeks following a pregnancy complicated by all types of hypertension (pre-eclampsia, gestational hypertension, essential hypertension with and without superimposed pre-eclampsia). We performed statistical analysis using Spearmans rho to examine for correlations with maternal and fetal characteristics. RESULTS 2.1% women had poor renal function at 6 weeks after delivery with a GFR <60ml/min/1.73m(2). Older mothers were more likely to have a lower GFR (p=0.001). Women with poor renal function at 6 weeks were more likely to have had a low birth weight baby (p=0.002). The median birth weight for women with GFR<60ml/min/1.73m(2) was 2.85kg as opposed to 3.23kg for women with a GFR >60ml/min/1.73m(2). CONCLUSIONS Clinically significant renal impairment following a hypertensive pregnancy is a rare. Advancing maternal age represents an important risk factor for on-going renal disease in this population. Small babies are more likely in a hypertensive pregnancy [2] and may also represent a marker for poorer maternal health after birth in this population.