Prevalence of pre-eclampsia and adverse pregnancy outcomes in women with pre-existing cardiomyopathy: a multi-centre retrospective cohort study.

Pre-eclampsia is associated with postnatal cardiac dysfunction; however, the nature of this relationship remains uncertain. This multicentre retrospective cohort study aimed to determine the prevalence of pre-eclampsia in women with pre-existing cardiac dysfunction (left ventricular ejection fraction < 55%) and explore the relationship between pregnancy outcome and pre-pregnancy cardiac phenotype. In this cohort of 282 pregnancies, pre-eclampsia prevalence was not significantly increased (4.6% [95% C.I 2.2-7.0%] vs. population prevalence of 4.6% [95% C.I. 2.7-8.2], p = 0.99); 12/13 women had concurrent obstetric/medical risk factors for pre-eclampsia. The prevalence of preterm pre-eclampsia (< 37 weeks) and fetal growth restriction (FGR) was increased (1.8% vs. 0.7%, p = 0.03; 15.2% vs. 5.5%, p < 0.001, respectively). Neither systolic nor diastolic function correlated with pregnancy outcome. Antenatal ß blockers (n = 116) were associated with lower birthweight Z score (adjusted difference - 0.31 [95% C.I. - 0.61 to - 0.01], p = 0.04). To conclude, this study demonstrated a modest increase in preterm pre-eclampsia and significant increase in FGR in women with pre-existing cardiac dysfunction. Our results do not necessarily support a causal relationship between cardiac dysfunction and pre-eclampsia, especially given the population's background risk status. The mechanism underpinning the relationship between cardiac dysfunction and FGR merits further research but could be influenced by concomitant ß blocker use.

Pre-eclampsia: the Potential of GSNO Reductase Inhibitors.

PURPOSE OF REVIEW: Pre-eclampsia remains a leading worldwide cause of maternal death and of perinatal morbidity. There remains no definitive treatment except delivery of the fetus. RECENT FINDINGS: Recent insights into the cardiovascular changes that are evident prior to, during, and persist after pre-eclampsia have improved understanding of the underlying pathophysiology-disruption of normal endothelial function and decreased nitric oxide bioavailability. S-nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol that acts as a NO pool and, by replenishing or preventing the breakdown of GSNO, endothelial dysfunction can be ameliorated. GSNO reductase inhibitors are a novel class of drug that can increase NO bioavailability. GSNO reductase inhibitors have demonstrated improvement of endothelial dysfunction in animal models, and in vivo human studies have shown them to be well tolerated. GSNOR inhibitors offer a potentially promising option for the management of pre-eclampsia.

Antenatal tests of fetal wellbeing.

In current obstetric practice, there is frequently a need to assess fetal wellbeing. This is particularly so in those fetuses at risk, including the small-for-gestational-age fetus or the fetus of a mother who presents with reduced fetal movements or who has an obstetric complication such as pre-eclampsia. It is important that the clinician is able to assess fetal wellbeing in such cases, especially in preterm gestations, when inappropriate delivery could have serious adverse consequences. In this paper, we review the current evidence for the use and the limitations of widely used methods of antenatal monitoring including the use of cardiotocography, biophysical profile, and ultrasound-derived parameters including umbilical artery, middle cerebral artery, and ductus venosus Doppler flow.

S-Nitrosoglutathione improves haemodynamics in early-onset pre-eclampsia.

AIMS: To determine the effects of in vivo S-nitrosoglutathione (GSNO) infusion on cardiovascular function, platelet function, proteinuria and biomarker parameters in early-onset pre-eclampsia. METHODS: We performed an open-label dose-ranging study of GSNO in early-onset pre-eclampsia. Six women underwent GSNO infusion whilst receiving standard therapy. The dose of GSNO was increased incrementally to 100 µg min(-1) whilst maintaining blood pressure of >140/80 mmHg. Aortic augmentation index, aortic pulse wave velocity, blood pressure and maternal-fetal Doppler parameters were measured at each dose. Platelet P-selectin, protein-to-creatinine ratio and soluble anti-angiogenic factors were measured pre- and postinfusion. RESULTS: Augmentation index fell at 30 µg min(-1) S-nitrosoglutathione (-6%, 95% confidence interval 0.6 to 13%), a dose that did not affect blood pressure. Platelet P-selectin expression was reduced [mean (interquartile range), 6.3 (4.9-7.6) vs. 4.1 (3.1-5.7)% positive, P = 0.03]. Soluble endoglin levels showed borderline reduction (P = 0.06). There was a borderline significant change in pre-to-postinfusion protein-to-creatinine ratio [mean (interquartile range), 0.37 (0.09-0.82) vs. 0.23 (0.07-0.49) g mmol(-1) , P = 0.06]. Maternal uterine and fetal Doppler pulsatility indices were unchanged. CONCLUSIONS: In early-onset pre-eclampsia, GSNO reduces augmentation index, a biomarker of small vessel tone and pulse wave reflection, prior to affecting blood pressure. Proteinuria and platelet activation are improved at doses that affect blood pressure minimally. These effects of GSNO may be of therapeutic potential in pre-eclampsia, a condition for which no specific treatment exists. Clinical studies of GSNO in early-onset pre-eclampsia will determine whether these findings translate to improvement in maternal and/or fetal outcome.

A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.

OBJECTIVE: Our objective was to investigate the extent of changes in maternal cardiovascular function, lipids and renal function during normal pregnancy from preconception to postpartum period. METHODS: In this prospective study of 54 normal pregnancies, detailed hemodynamics were performed preconception, at 6, 23 and 33 weeks during pregnancy and 16 weeks postpartum. RESULTS: Although the greatest reduction of blood pressures (BPs) and augmentation index occurred in early pregnancy (Δbrachial systolic: 4 ±â€Š7  mmHg, Δcentral systolic: 7 ±â€Š7  mmHg; P < 0.001), the peripheral vascular resistance reached a nadir (Δ: 222 ±â€Š215 dynes.s.cm; P < 0.001) by the second trimester. The greatest increase in cardiac output occurred by the second trimester (Δ: 0.6 ±â€Š1 l/min, P < 0.001), whereas the heart rate increased maximally by the third trimester (Δ: 13 ±â€Š11  bpm; P = 0.001). The unadjusted aortic pulse wave velocity decreased in the second trimester (P < 0.001), however, when adjusted for mean arterial pressure this was not significant (P = 0.06). BPs were lower (Δ brachial systolic: 5 ±â€Š8  mmHg; P < 0.001) and augmentation index higher (Δ: 2.5 ±â€Š7%; P = 0.01) postpartum than preconception. The cholesterol:high-density lipoprotein ratio, serum low density lipoprotein and serum creatinine all fell (P < 0.001) in the first trimester. CONCLUSION: We have shown that normal pregnancy, irrespective of parity, is associated with significant changes commencing very early in pregnancy, continuing throughout pregnancy, and some of these changes persisted postpartum. Therefore, first trimester or postpartum baselines will underestimate the true extent of pregnancy-related changes. Prospective studies of cardiovascular function from preconception to postpartum will provide more reliable estimates of the influence of cardiovascular maladaptation during pregnancy complications and their effect on longer term cardiovascular function.

The nitric oxide pathway and possible therapeutic options in pre-eclampsia.

Pre-eclampsia is a serious multisystem disorder with diverse clinical manifestations. Although not causal, endothelial dysfunction and reduced nitric oxide bioavailability are likely to play an important role in the maternal and fetal pathophysiology of this condition. Lack of treatment modalities that can target the underlying pathophysiological changes and reverse the endothelial dysfunction frequently leads to iatrogenic preterm delivery of the fetus, causing neonatal morbidity and mortality, and the condition itself is associated with short- and longer term maternal morbidity and mortality. Drugs that target various components of the nitric oxide-soluble guanylyl cyclase pathway can help to increase NO bioavailability. The purpose of this review is to outline the current status of clinical research involving these therapeutic modalities in the context of pre-eclampsia, with the focus being on the following: nitric oxide donors, including organic nitrates and S-nitrosothiols; l-arginine, the endogenous precursor of NO; inhibitors of cyclic guanosine 3',5'-monophosphate breakdown, including sildenafil; and other novel inhibitors of NO donor metabolism. The advantages and limitations of each modality are outlined, and scope for development into established therapeutic options for pre-eclampsia is explored.

The feasibility of prospectively studying maternal cardiovascular changes from before conception.

There is compelling evidence that factors before pregnancy and around implantation may have a bearing on maternal cardiovascular adaptation to pregnancy and subsequent pregnancy outcome. Prospective studies from before pregnancy are associated with difficulties in recruitment, low conception rates, early pregnancy loss and low retention of participants during pregnancy and postpartum follow-up. The objective of this study was to establish the feasibility of recruiting to; conducting and completing a prospective cohort study from before pregnancy to the postpartum period. One-hundred and forty-three women planning to conceive were recruited. They underwent detailed cardiovascular measurements including brachial and central blood pressures, cardiac output, aortic stiffness and pulse wave reflection, metabolic function and platelet aggregation. Once pregnant, the cardiovascular assessments were repeated at intervals throughout pregnancy and postpartum. Of 143 women, 101 women conceived within 18 months. Seventy-one had viable pregnancies at 10-14 weeks. Among the 70 live-births, three women developed preeclampsia (PE) and two had intrauterine growth restriction. Two were lost to follow-up. It is feasible to recruit women who are planning to conceive, conduct prepregnancy cardiovascular assessments and follow them up during pregnancy. Based on the current data, approximately half the women recruited will have healthy ongoing pregnancies. This information would allow the design of a study, powered for pregnancy complications such as PE, to enable investigation of the 'cause and effect' relationship between abnormal cardiovascular function and pregnancy complications.

Mid-trimester maternal heart rate is related to neonatal birth weight.

OBJECTIVE(S): We sought to establish the relationship between maternal mid-trimester heart rate (HR) and neonatal birth weight in women at high a priori risk of preeclampsia. STUDY DESIGN: Ninety-nine women were recruited following second trimester uterine artery Doppler assessment. Maternal blood pressure (BP) and HR were measured between 23(+4) and 30(+5) weeks gestation and neonatal birth weight was expressed as a z-score. The relationship between the parameters was investigated using Pearson's correlation coefficient. RESULTS: There was a significant positive correlation between maternal HR and neonatal birth weight z-score, r = 0.22 (95% CI: 0.02-0.40), p = 0.03. An inverse correlation was found between uterine artery Doppler pulsatility index (PI) and maternal HR, r = -0.43 (95% CI: 0.01-0.40), p = 0.0001, and neonatal birth weight, r = -0.3 (95% CI: -0.47 to -0.10), p = 0.004. For neonatal birth weight z-score <-1.65, r = 0.69 (95% CI: 0.15-0.91), p = 0.02. There was no relationship between BP and uterine artery Doppler or neonatal birth weight. CONCLUSION: The finding of a continuous relationship between maternal HR and neonatal birth weight prior to the onset of fetal growth restriction is novel, suggesting that maternal cardiovascular adaptation is reflected by neonatal birth weight. Lower maternal HR is associated with lower neonatal birth weight and vice versa. Further, we confirm the reported associations between uterine artery Doppler PI and both maternal HR and neonatal birth weight.

Cardiovascular function in women with recurrent miscarriage, pre-eclampsia and/or intrauterine growth restriction.

OBJECTIVE: To investigate prepregnancy cardiovascular function and risk factors in women with previous pregnancy complications. METHODS: Thirty-four women with previous normal pregnancy (controls), 26 with unexplained recurrent miscarriage (RM) and 14 with pre-eclampsia (PE) and/or intrauterine growth restriction (IUGR), planning to conceive were recruited. Brachial and central blood pressures (BP), cardiac output (CO), peripheral vascular resistance (PVR), aortic stiffness, blood biochemistry and platelet aggregation were assessed. RESULTS: Women with previous PE/IUGR had higher brachial diastolic BP (78 ± 9 vs 71 ± 7 mmHg; p = 0.03), central systolic BP (107 ± 10 vs 99 ± 8 mmHg; p = 0.03), mean arterial pressure (92 ± 10 vs 84 ± 8 mmHg; p = 0.01) and PVR (1499 ± 300 vs 1250 ± 220 dynes.s(-1) cm(-5); p = 0.005), than the controls. No differences were observed in either cardiovascular function or blood biochemistry in women with unexplained RM compared with the controls. Women with previous PE/IUGR though not with RM had a stronger family history of cardiovascular disease (CVD) than controls. CONCLUSIONS: Women with previous PE and/or IUGR had higher BP and PVR compared with controls, which may predispose them to CVD later in life. However, in the absence of underlying vascular pathology, women with unexplained RM did not have abnormal cardiovascular function. Prepregnancy period provides an opportunity to identify cardiovascular risks in relation to previous obstetric history.

Maternal cardiovascular changes from pre-pregnancy to very early pregnancy.

OBJECTIVE: Our aim was to assess changes in maternal cardiovascular haemodynamics, including central blood pressure (BP), wave reflections and aortic stiffness, from pre-pregnancy to very early pregnancy. METHODS: Fifty-six healthy nulliparous or women with previous uncomplicated pregnancy were studied prior to conception and in very early pregnancy. Assessments of brachial and central BPs, pulse wave reflection quantified by augmentation index (AIx), aortic stiffness using carotid femoral pulse wave velocity (aPWV) and cardiac output (CO) were performed. RESULTS: Pregnancy measurements were obtained at median gestational age of 6.3 weeks [interquartile range (IQR) 6-6.5 weeks] from the last menstrual period. Whilst heart rate (HR) increased from 67  ±â€Š 10 to 71  ±  10  bpm. (P  =  0.001), brachial SBP, DBP and central SBP were all lower than the pre-pregnancy values (109  ±â€Š 10 to 104  ±â€Š 7 mmHg, 72  ±  8 to 65  ±  6 mmHg and 99  ±â€Š 10 to 92  ±â€Š 7 mmHg, respectively; P  <  0.001 for all). AIx adjusted for HR fell (19  ±â€Š 10 to 13  ±â€Š 9%; P  =  0.001) as did peripheral vascular resistance (PVR; 1234 ±â€Š229 to 1128  ±  280 dynes/s/cm; P = 0.003). aPWV adjusted for mean arterial pressure (MAP) was unchanged (5.3  ±â€Š 0.6 to 5.1  ±  0.6m/s; P  =  0.2). CONCLUSION: Significant changes occur in brachial and central BP, AIx and PVR in successful, ongoing pregnancies, by about 6-7 weeks gestation; much earlier than has hitherto been assumed. Using late first trimester data as 'baseline' cannot be relied on to estimate the extent of cardiovascular changes in normal pregnancy. Future studies of cardiovascular changes in pregnancy should, therefore, have a pre-pregnancy starting point.

Drug development in preeclampsia: a 'no go' area?

Drug development in pregnancy and particularly in preeclampsia has been long neglected. Preeclampsia is a leading cause of maternal mortality, and early-onset preeclampsia can result in serious long-lasting consequences to the neonate. Many treatments have been trialed with varying success including vitamin supplementation, low-molecular-weight heparins, and aspirin. In this commentary, we particularly focus on the current status of drugs in development specifically aimed at preeclampsia. We outline the current understanding of the causes of the endothelial dysfunction seen in preeclampsia and, as such, potential therapeutic targets. With treatment of preeclampsia being largely unchanged in decades, there is an urgent need for novel therapies particularly those directed at the underlying causes that may allow for extremely preterm delivery, and its myriad consequences, to be avoided.