Thomas R. Everett

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 (&Dgr;brachial systolic: 4 ± 7 mmHg, &Dgr;central systolic: 7 ± 7 mmHg; P < 0.001), the peripheral vascular resistance reached a nadir (&Dgr;: 222 ± 215 dynes.s−1.cm−5; P < 0.001) by the second trimester. The greatest increase in cardiac output occurred by the second trimester (&Dgr;: 0.6 ± 1 l/min, P < 0.001), whereas the heart rate increased maximally by the third trimester (&Dgr;: 13 ± 11 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 (&Dgr; brachial systolic: 5 ± 8 mmHg; P < 0.001) and augmentation index higher (&Dgr;: 2.5 ± 7%; 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.

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 ± 10 to 71 ± 10 bpm. (P = 0.001), brachial SBP, DBP and central SBP were all lower than the pre-pregnancy values (109 ± 10 to 104 ± 7mmHg, 72 ± 8 to 65 ± 6mmHg and 99 ± 10 to 92 ± 7mmHg, respectively; P < 0.001 for all). AIx adjusted for HR fell (19 ± 10 to 13 ± 9%; P = 0.001) as did peripheral vascular resistance (PVR; 1234 ± 229 to 1128 ± 280 dynes/s/cm5; P = 0.003). aPWV adjusted for mean arterial pressure (MAP) was unchanged (5.3 ± 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.

Beyond the placental bed: Placental and systemic determinants of the uterine artery Doppler waveform

The uterine artery Doppler waveform has been extensively investigated, though its widespread clinical use as a predictor of adverse pregnancy outcome remains under debate. The determinants of the waveform have classically been ascribed to transformation of the spiral arteries and the development of a low resistance uteroplacental circulation, failure of which predisposes to pre-eclampsia, fetal growth restriction and other adverse outcomes. It has become increasingly evident that although spiral artery transformation determines in some part the characteristics of the Doppler waveform, factors pertaining to maternal vascular and endothelial function are also important.

Impact of ovulation and implantation timing on first-trimester crown-rump length and gestational age

To determine the impact of ovulation and implantation timing on first‐trimester crown–rump length (CRL) and the derived gestational age (GA).

Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester

OBJECTIVE To assess the relationship between uterine artery Doppler pulsatility index (PI) and maternal global arterial stiffness and aortic stiffness in women at high a priori risk of preeclampsia in the late second trimester of pregnancy. METHODS A prospective cohort study was performed. 99 women were recruited from the high-risk obstetric ultrasound clinic in the second trimester; median (±IQR) age and gestation were 33 (29-37) years and 23(+6) (23(+3)-24(+4)) weeks respectively. Transabdominal uterine artery Doppler was performed and mean values recorded. Women returned at a later date, median gestation (±IQR) 26(+5) (25(+6)-28(+0)) weeks, for measurement of blood pressure, augmentation index (AIx) and aortic pulse wave velocity (aPWV). RESULTS Uterine artery PI is positively associated with both AIx (r = 0.4, P <0.0001, 95% CI: 0.22-0.55) and aPWV (r = 0.22, P = 0.03, 95% CI: 0.02-0.40). No relationship was found between uterine artery PI and mean arterial pressure or pulse pressure. AIx was significantly higher in women with uterine artery PI > 1.45 (P = 0.003, 95% CI: 3.1-14.9) but not aPWV (P = 0.45). AIx, but not aPWV, was significantly higher in women who developed preeclampsia (14% vs 9%, 95% CI: 2.0-8.6, P = 0.0018) or IUGR (11% vs 9%, 95% CI: 0.3-4.2, P = 0.027). AIx showed a negative correlation with birth weight z-score (r = -0.25, 95% CI: -0.43 to -0.06, P = 0.013). CONCLUSION Increasing uterine artery Doppler PI reflects impaired placentation and increasing risk of preeclampsia. We show a positive association between uterine artery Doppler PI and both global arterial and aortic stiffness. We also show that increased maternal arterial stiffness is associated with a lower birth weight. These findings may represent evidence of an early effect of impaired placentation on the maternal vasculature. Alternatively, given the association between preeclampsia and later cardiovascular disease, ineffective placentation may result from impaired arterial function.

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.

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.

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.

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.