Amita A. Mahendru

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.

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.

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.

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.

Change in maternal cardiac output from preconception to mid‐pregnancy is associated with birth weight in healthy pregnancies

Birth weight (BW) is thought to be determined by maternal health and genetic, nutritional and placental factors, the latter being influenced by anatomical development and perfusion. Maternal cardiovascular changes contribute to uteroplacental perfusion; however, they have not yet been investigated in relation to fetal growth or BW. Our aim was to explore the relationship between maternal cardiovascular adaptation, fetal growth and BW in healthy pregnancies.

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

Abstract 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.

Association Between Prepregnancy Cardiovascular Function and Subsequent Preeclampsia or Fetal Growth RestrictionNovelty and Significance

Preeclampsia and fetal growth restriction during pregnancy are associated with increased risk of maternal cardiovascular disease later in life. It is unclear whether this association is causal or driven by similar antecedent risk factors. Clarification requires recruitment before conception which is methodologically difficult with high attrition rates and loss of outcome numbers to nonconception/miscarriage. Few prospective studies have, therefore, been adequately powered to address these questions. We recruited 530 healthy women (mean age: 35.0 years) intending to conceive and assessed cardiac output, cardiac index, stroke volume, total peripheral resistance, mean arterial pressure, and heart rate before pregnancy. Participants were followed to completion of subsequent pregnancy with repeat longitudinal assessments. Of 356 spontaneously conceived pregnancies, 15 (4.2%) were affected by preeclampsia and fetal growth restriction. Women who subsequently developed preeclampsia/fetal growth restriction had lower preconception cardiac output (4.9 versus 5.8 L/min; P=0.002) and cardiac index (2.9 versus 3.3 L/min per meter2; P=0.031) while mean arterial pressure (87.1 versus 82.3 mm Hg; P=0.05) and total peripheral resistance (1396.4 versus 1156.1 dynes sec cm−5; P<0.001) were higher. Longitudinal trajectories for cardiac output and total peripheral resistance were similar between affected and healthy pregnancies, but the former group showed a more exaggerated fall in mean arterial pressure in the first trimester, followed by a steeper rise and a steeper fall to postpartum values. Significant relationships were observed between cardiac output, total peripheral resistance, and mean arterial pressure and gestational epoch. We conclude that in healthy women, an altered prepregnancy hemodynamic phenotype is associated with the subsequent development of preeclampsia/fetal growth restriction.