Maternal cardiac function, uterine artery hemodynamics and natriuretic peptides at 22-24 weeks of gestation and subsequent development of hypertensive disorders of pregnancy.

INTRODUCTION: Maternal cardiac dysfunction as well as abnormal uterine artery (UtA) Doppler are associated with hypertensive disorders of pregnancy (HDP), but their relation is unclear. We investigated the correlation between maternal cardiac function, UtA hemodynamics and natriuretic peptides, and explored differences between women who subsequently developed HDP and those who did not. MATERIAL AND METHODS: This was a prospective cross-sectional cohort study of 347 pregnant women at 22-24 weeks. Maternal cardiac function and systemic hemodynamics were investigated at baseline and after 90 seconds of passive leg raising using impedance cardiography. Preload reserve was defined as percent change (Δ%) in stroke volume and cardiac output from baseline to passive leg raising. UtA hemodynamics was studied using Doppler ultrasonography. UtA blood flow, resistance and pulsatility index were calculated. Fasting venous blood samples were analyzed for natriuretic peptides (pro atrial natriuretic peptide [proANP], N-terminal pro brain natriuretic peptide [Nt-proBNP] and C-type natriuretic peptide [CNP]). The course and outcome of pregnancy were recorded. RESULTS: At baseline, ProANP correlated significantly with cardiac output (r = -0.122; P = .023) and left cardiac work index (r = -0.112; P = .037), whereas Nt-ProBNP correlated significantly with acceleration index (r = .127; P = .018) and velocity index (r = -0.111; P = .039. CNP correlated significantly with UtA blood flow (r = .118; P = .028) and resistance (r = -0.112; P = .037) but not with UtA pulsatility index (r = .034; P = .523). None of the natriuretic peptides correlated with preload reserve. At 22-24 weeks, women who subsequently developed HDP had lower UtA blood flow (552 vs 692 mL/min; P = .028), higher UtA resistance (0.28 vs .17 mmHg/mL/min; P = .004) and higher mean UtA pulsatility index (1.12 vs .84; P < .001) compared with those who did not; however, the natriuretic peptide levels were similar in the two groups. Women developing HDP had a significantly higher increase in stroke volume and cardiac output and more reduction in systemic vascular resistance following passive leg raising compared with the reference group. Left cardiac work index, acceleration index and velocity index decreased following passive leg raising in the reference group but increased in women who later developed HDP. CONCLUSIONS: ProANP correlated with cardiac output and cardiac work, Nt-proBNP with indices of cardiac contractility, and CNP with UtA blood flow and resistance. None of these natriuretic peptides measured at 22-24 weeks of gestation reflected cardiac preload reserve or predicted development of HDP.

Sexual Dimorphism in Umbilical Vein Blood Flow During the Second Half of Pregnancy: A Longitudinal Study.

OBJECTIVES: To investigate gestational age-specific serial changes in umbilical vein (UV) volume blood flow during the second half of normal pregnancy and establish sex-specific reference ranges. METHODS: This work was a prospective longitudinal study of singleton low-risk pregnancies. The UV diameter and maximum blood flow velocity were serially measured by sonography at the intra-abdominal portion of the UV over 19 to 41 weeks. Umbilical vein volume blood flow was calculated and normalized for estimated fetal weight. RESULTS: One hundred seventy-nine women and their fetuses (87 male and 92 female) were included in the final analysis, and a total of 746 observations were used to construct sex-specific reference intervals. We found no statistically significant sex-specific differences in the UV parameters examined. However, the temporal development patterns of normalized UV volume blood flow appeared to differ between male and female fetuses during the second half of pregnancy, with crossovers at 24 and 32 weeks' gestation. CONCLUSIONS: Umbilical vein volume blood flow is similar among male and female fetuses in quantitative terms, but the pattern of gestational age-dependent temporal changes may be different, which may have important physiologic implications with regard to in utero development and maturation of the fetoplacental unit.

Longitudinal reference ranges for maternal plasma laeverin, and its role as a potential biomarker of preeclampsia.

BACKGROUND: Laeverin is a placenta-specific membrane-bound aminopeptidase. In this study we wanted to: 1) serially measure plasma levels of laeverin in healthy women during the second half of pregnancy and postpartum, 2) determine whether laeverin is differently expressed at 22-24 weeks in women who later develop preeclampsia compared to controls, 3) compare laeverin protein expression in placenta and umbilical vein serum in healthy and preeclamptic pregnancies at birth. METHODS: Plasma was obtained serially, approximately every 4-weeks, from 53 healthy women with uncomplicated pregnancies during 22+0 to 39+6 weeks of gestation, and at 22-24 weeks from 15 women who later developed preeclampsia. Enzyme-linked immunosorbent assay was used to measure laeverin protein concentration. Serum from healthy non-pregnant premenopausal women (n = 10), menopausal women (n = 10) and men (n = 11) were used as negative controls. Protein extracts from placental tissue were obtained after birth from healthy- (n = 11) and preeclamptic women (n = 13). Paired umbilical artery and vein serum samples from the neonates (n = 10) of healthy mothers were also analyzed. Multilevel modeling was used to determine the reference centiles. Differences between groups were analyzed using Student's t-test. RESULTS: Healthy pregnant women at term (37-40 weeks) had significantly higher plasma levels of laeverin (mean 4.95 ± 0.32 ng/mL; p < 0.0001) compared to men (mean 0.18 ± 0.31 ng/mL), non-pregnant premenopausal women (mean 0.77 ± 0.26 ng/mL) and postmenopausal women (mean 0.57 ± 0.40 ng/mL). Maternal plasma laeverin levels decreased with advancing gestation, from 6.96 ± 0.32 ng/mL at 22-24 weeks to 4.95 ± 0.32 ng/mL at term (p < 0.0001) in uncomplicated pregnancies. Half of the women who developed preeclampsia had plasma laeverin levels below the 5th percentile at 22-24 weeks gestation. However, laeverin levels were 1.6 fold higher in preeclamptic compared to healthy placentas (p = 0.0071). Umbilical venous samples of healthy neonates (n = 38) had higher (p = 0.001) mean levels of laeverin (16.63 ± 0.73 ng/mL), compared to neonates of preeclamptic (n = 14) mothers (12.02 ± 1.00 ng/mL). Postpartum plasma levels of laeverin decreased in healthy and preeclamptic women with a half-life of 3 and 5 days, respectively. CONCLUSIONS: Maternal plasma levels of laeverin decrease with advancing gestation during the second half of normal pregnancy and lower levels measured at 22-24 weeks might be associated with the development of preeclampsia later in gestation.

Sex differences in umbilical artery Doppler indices: a longitudinal study.

BACKGROUND: Sexual dimorphism in placental size and function has been described. Whether this influences the clinically important umbilical artery (UA) waveform remains controversial, although a few cross-sectional studies have shown sex differences in UA pulsatility index (PI). Therefore, we tested whether fetal sex influences the UA Doppler indices during the entire second half of pregnancy and aimed to establish sex-specific reference ranges for UA Doppler indices if needed. METHODS: Our main objective was to investigate gestational age-associated changes in UA Doppler indices during the second half of pregnancy and compare the values between male and female fetuses. This was a prospective longitudinal study in women with singleton low-risk pregnancies during 19-40 weeks of gestation. UA Doppler indices were serially obtained at a 4-weekly interval from a free loop of the umbilical cord using color-directed pulsed-wave Doppler ultrasonography. Sex-specific reference intervals were calculated for the fetal heart rate (HR), UA PI, resistance index (RI), and systolic/diastolic ratio (S/D) using multilevel modeling. RESULTS: Complete data from 294 pregnancies (a total of 1261 observations from 152 male and 142 female fetuses) were available for statistical analysis, and sex-specific reference ranges for the UA Doppler indices and fetal HR were established for the last half of pregnancy. UA Doppler indices were significantly associated with gestational age (P < 0.0001) and fetal HR (P < 0.0001). Female fetuses had 2-8% higher values for UA Doppler indices than male fetuses during gestational weeks 20+0-36+6 (P < 0.05), but not later. Female fetuses had higher HR from gestational week 26+0 until term (P < 0.05). CONCLUSIONS: We have determined gestational age-dependent sex differences in UA Doppler indices and fetal HR during the second half of pregnancy, and correspondingly established new sex-specific reference ranges intended for refining diagnostics and monitoring individual pregnancies.

Exploring sexual dimorphism in placental circulation at 22-24 weeks of gestation: A cross-sectional observational study.

INTRODUCTION: Placental blood flow is closely associated with fetal growth and wellbeing. Recent studies suggest that there are differences in blood flow between male and female fetuses. We hypothesized that sexual dimorphism exists in fetal and placental blood flow at 22-24 weeks of gestation. METHODS: This was a prospective cross-sectional study of 520 healthy pregnant women. Blood flow velocities of the middle cerebral artery (MCA), umbilical artery (UA), umbilical vein (UV) and the uterine arteries (UtA) were measured using Doppler ultrasonography. UV and UtA diameters were measured using two-dimensional ultrasonography and power Doppler angiography. Volume blood flows (Q) of the UV and UtA were calculated. Maternal haemodynamics was assessed with impedance cardiography. UtA resistance (Ruta) was computed as MAP/Quta. RESULTS: UA PI was significantly (p = 0.008) higher in female fetuses (1.19 ± 0.15) compared with male fetuses (1.15 ± 0.14). MCA PI, cerebro-placental ratio (MCA PI/UA PI), Quv, UtA PI, Quta and Ruta were not significantly different between groups. At delivery, the mean birth weight and placental weight of female infants (3504 g and 610 g) were significantly (p = 0.0005 and p = 0.039) lower than that of the male infants (3642 g and 634 g). DISCUSSION: We have demonstrated sexual dimorphism in UA PI, a surrogate for placental vascular resistance, at 22-24 weeks of gestation. Therefore, it would be useful to know when this difference emerges and whether it translates into blood flow differences that may impact upon the fetal growth trajectory.

Static and Functional Hemodynamic Profiles of Women with Abnormal Uterine Artery Doppler at 22-24 Weeks of Gestation.

OBJECTIVE: To compare cardiac function, systemic hemodynamics and preload reserve of women with increased (cases) and normal (controls) uterine artery (UtA) pulsatility index (PI) at 22-24 weeks of gestation. MATERIALS AND METHODS: A prospective cross-sectional study of 620 pregnant women. UtA blood flow velocities were measured using Doppler ultrasonography, and PI was calculated. Mean UtA PI ≥ 1.16 (90th percentile) was considered abnormal. Maternal hemodynamics was investigated at baseline and during passive leg raising (PLR) using impedance cardiography (ICG). Preload reserve was defined as percent increase in stroke volume (SV) 90 seconds after passive leg raising compared to baseline. RESULTS: Mean UtA PI was 1.49 among cases (n = 63) and 0.76 among controls (n = 557) (p < 0.0001). Eighteen (28.6%) cases and 53 (9.5%) controls developed pregnancy complications (p <0.0001). The mean arterial pressure and systemic vascular resistance were 83 mmHg and 1098.89±293.87 dyne s/cm5 among cases and 79 mmHg and 1023.95±213.83 dyne s/cm5 among controls (p = 0.007 and p = 0.012, respectively). Heart rate, SV and cardiac output were not different between the groups. Both cases and controls responded with a small (4-5%) increase in SV in response to PLR, but the cardiac output remained unchanged. The preload reserve was not significantly different between two groups. CONCLUSION: Pregnant women with abnormal UtA PI had higher blood pressure and systemic vascular resistance, but similar functional hemodynamic profile at 22-24 weeks compared to controls. Further studies are needed to clarify whether functional hemodynamic assessment using ICG can be useful in predicting pregnancy complications.