Nitric oxide donor increases umbilical vein blood flow and fetal oxygenation in fetal growth restriction. A pilot study.

INTRODUCTION: To evaluate the maternal and fetal hemodynamic effects of treatment with a nitric oxide donor and oral fluid in pregnancies complicated by fetal growth restriction. METHODS: 30 normotensive participants with early fetal growth restriction were enrolled. 15 participants were treated until delivery with transdermal glyceryl trinitrate and oral fluid intake (Treated group), and 15 comprised the untreated group. All women underwent non-invasive assessment of fetal and maternal hemodynamics and repeat evaluation 2 weeks later. RESULTS: In the treated group, maternal hemodynamics improved significantly after two weeks of therapy compared to untreated participants. Fetal hemodynamics in the treated group showed an increase in umbilical vein diameter by 18.87 % (p < 0.01), in umbilical vein blood flow by 48.16 % (p < 0.01) and in umbilical vein blood flow corrected for estimated fetal weight by 30.03 % (p < 0.01). In the untreated group, the characteristics of the umbilical vein were unchanged compared to baseline. At the same time, the cerebro-placental ratio increased in the treated group, while it was reduced in the untreated group, compared to baseline values. The treated group showed a higher birthweight centile (p = 0.03) and a lower preeclampsia rate (p = 0.04) compared to the untreated group. DISCUSSION: The combined therapeutic approach with nitric oxide donor and oral fluid intake in fetal growth restriction improves maternal hemodynamics, which becomes more hyperdynamic (volume-dominant). At the same time, in the fetal circuit, umbilical vein flow increased and fetal brain sparing improved. Although a modest sample size, there was less preeclampsia and a higher birthweight suggesting beneficial maternal and fetal characteristics of treatment.

Maternal cardiovascular profile is altered in the preclinical phase of normotensive early and late intrauterine growth restriction.

BACKGROUND: The maternal cardiovascular profile of patients who develop late fetal growth restriction has yet to be well characterized, however, a subclinical impairment in maternal hemodynamics and cardiac function may be present before pregnancy and may become evident because of the hemodynamic alterations associated with pregnancy. OBJECTIVE: This study aimed to investigate if maternal hemodynamics and the cardiovascular profile might be different in the preclinical stages (22-24 weeks' gestation) in cases of early and late fetal growth restriction in normotensive patients. STUDY DESIGN: This was a prospective echocardiographic study of 1152 normotensive nulliparous pregnant women at 22 to 24 weeks' gestation. The echocardiographic evaluation included morphologic parameters (left ventricular mass index and relative wall thickness, left atrial volume index) and systolic and diastolic maternal left ventricular function (ejection fraction, left ventricular global longitudinal strain, E/A ratio, and E/e' ratio). Patients were followed until the end of pregnancy to note the development of normotensive early or late fetal growth restriction. RESULTS: Of the study cohort, 1049 patients had no complications, 73 were classified as having late fetal growth restriction, and 30 were classified as having early fetal growth restriction. In terms of left ventricular morphology, the left ventricular end-diastolic diameter was greater in uneventful pregnancies (4.84±0.28 cm) than in late (4.67±0.26 cm) and in early (4.55±0.26 cm) (P<.001) fetal growth restriction cases, whereas left ventricular end-systolic diameter was smaller in uneventful pregnancies (2.66±0.39 cm) than in late (2.83±0.40 cm) and in early (2.82±0.38 cm) (P<.001) fetal growth restriction cases. The relative wall thickness was slightly higher in early (0.34±0.05) and late (0.35±0.04) fetal growth restriction cases than in uneventful pregnancies (0.32±0.05) (P<.05). In terms of systolic left ventricular function, at 22 to 24 weeks' gestation, cardiac output was higher in uneventful pregnancies (6.58±1.07 L/min) than in late (5.40±0.97 L/min) and in early (4.76±1.05 L/min) (P<.001) fetal growth restriction cases with the lowest values in the early-onset group. Left ventricular global longitudinal strain was lower in appropriate for gestational age neonates (-21.6%±2.0%) and progressively higher in late (-20.1%±2.2%) and early (-18.5%±2.3%) (P<.001) fetal growth restriction cases. In terms of diastolic left ventricular function, the E/e' ratio showed intermediate values in the late fetal growth restriction group (7.90±2.73) when compared with the appropriate for gestational age group (7.24±2.43) and with the early fetal growth restriction group (10.76±3.25) (P<.001). The total peripheral vascular resistance was also intermediate in the late fetal growth restriction group (1300±199 dyne·s·cm-5) when compared with the appropriate for gestational age group (993±175 dyne·s·cm-5) and the early fetal growth restriction group (1488±255 dyne.s.cm-5) (P<.001). CONCLUSION: Early and late fetal growth restriction share similar maternal hemodynamic and cardiovascular profiles with a different degree of expression. These features are already present at 22 to 24 weeks' gestation and are characterized by a hypodynamic state. The degree of these cardiovascular changes may influence the timing of the manifestation of the disease; a hypovolemic, high resistance, low cardiac output state might be associated with early-onset fetal growth restriction, whereas a milder hypovolemic state seems to favor the development of the disease in the final stages of pregnancy.

NO donors on top of anti-hypertensive therapy reduces complications in chronic hypertensive pregnancies with hypodynamic circulation.

OBJECTIVES: Chronic hypertension is associated with significant adverse maternal and fetal outcomes that appear to be often associated to a hypodynamic circulation. Treatment of hypertensive disorders of pregnancy tailored on maternal hemodynamics might reduce or mitigate these complications. Our purpose was to assess the hemodynamic modifications induced by the addition of NO donors and increased oral fluid intake on top of standard antihypertensive therapy in hypodynamic chronic hypertensive patients. We further evaluated if the possible hemodynamic modification induced by NO donors and increased oral fluid intake might be associated to a reduction of the severity and rate of complications vs. patients on antihypertensive standard treatment. STUDY DESIGN: This was a case-control study of 321 chronic hypertensive patients with a hypodynamic circulation at the echocardiographic evaluation at 24 weeks' gestation. We included 160 controls (standard antihypertensive therapy) and 161 cases (standard therapy + NO donor patches + increased oral fluid intake). Student T test for paired and unpaired data, univariate logistic regression analysis, ROC curve analysis, and Cox Hazards Regression analysis were used as appropriate. RESULTS: At enrollment the hemodynamic parameters were similar between the two groups. After 3-4 weeks stroke volume (77 ± 19 mL vs. 69 ± 19 mL; p < 0.001), and cardiac output (6.2 ± 1.7 L vs. 5.0 ± 1.6 L; p < 0.001) were higher and total peripheral vascular resistance (1465 ± 469 dyne·s·cm-5 vs. 1814 ± 524 dyne·s·cm-5; p < 0.001) was lower in the cases vs controls. Superimposed preeclampsia, preterm delivery before 34 weeks, abruptio placentae, HELLP Syndrome, fetal growth restriction, and perinatal death were more represented in the standard treatment group vs NO treated patients (81% vs 53%; p < 0.001). In particular, the standard treatment group showed 48% fetal growth restriction vs 34% in the NO treated group (p < 0.011). The Cox proportional-hazards regression showed a lower proportion of event-free pregnancies in controls on standard treatment (HR 2.6; 95% CI 2.0-3.5; p < 0.0001), and a prolongation of pregnancies in CH cases complicated by fetal growth restriction taking NO donors (HR 0.29; 95% CI 0.19-0.43; p = 0.0001). CONCLUSIONS: The tailored treatment with NO donors and oral fluids of hypodynamic CH might have positive effects on the reduction or mitigations of adverse outcomes.

The cardiac-fetal-placental unit: fetal umbilical vein flow rate is linked to the maternal cardiac profile in fetal growth restriction.

BACKGROUND: The functional maternal-fetal hemodynamic unit includes fetal umbilical vein flow and maternal peripheral vascular resistance. OBJECTIVE: This study investigated the relationships between maternal and fetal hemodynamics in a population with suspected fetal growth restriction. STUDY DESIGN: This was a prospective study of normotensive pregnancies referred to our outpatient clinic for a suspected fetal growth restriction. Maternal hemodynamics measurement was performed, using a noninvasive device (USCOM-1A) and a fetal ultrasound evaluation to assess fetal biometry and velocimetry Doppler parameters. Comparisons among groups were performed with 1-way analysis of variance with Student-Newman-Keuls correction for multiple comparisons and with Kruskal-Wallis test where appropriate. The Spearman rank coefficient was used to assess the correlation between maternal and fetal hemodynamics. Pregnancies were observed until delivery. RESULTS: A total of 182 normotensive pregnancies were included. After the evaluation, 54 fetuses were classified as growth restricted, 42 as small for gestational age, and 86 as adequate for gestational age. The fetus with fetal growth restriction had significantly lower umbilical vein diameter (P<.0001), umbilical vein velocity (P=.02), umbilical vein flow (P<.0001), and umbilical vein flow corrected for fetal weight (P<.01) than adequate-for-gestational-age and small-for-gestational-age fetuses. The maternal hemodynamic profile in fetal growth restriction was characterized by elevated systemic vascular resistance and reduced cardiac output. The umbilical vein diameter was positively correlated to maternal cardiac output (rs=0.261), whereas there was a negative correlation between maternal systemic vascular resistance (rs=-0.338) and maternal potential energy-to-kinetic energy ratio (rs=-0267). The fetal umbilical vein time averaged max velocity was positively correlated to maternal cardiac output (rs=0.189) and maternal inotropy index (rs=0.162), whereas there was a negative correlation with maternal systemic vascular resistance (rs=-0.264) and maternal potential energy-to-kinetic energy ratio (rs=-0.171). The fetal umbilical vein flow and the flow corrected for estimated fetal weight were positively correlated with maternal cardiac output (rs=0.339 and rs=0.297) and maternal inotropy index (rs=0.217 and r=0.336), whereas there was a negative correlation between maternal systemic vascular resistance (rs=-0.461 and rs=-0.409) and maternal potential energy-to-kinetic energy ratio (rs=-0.336 and rs=-0.408). CONCLUSION: Maternal and fetal hemodynamic parameters were different in the 3 groups of fetuses: fetal growth restriction, small for gestational age, and adequate for gestational age. Maternal hemodynamic parameters were closely and continuously correlated with fetal hemodynamic features. In particular, a maternal hemodynamic profile with high systemic vascular resistance, low cardiac output, reduced inotropism, and hypodynamic circulation was correlated with a reduced umbilical vein flow and increased umbilical artery pulsatility index. The mother, placenta, and fetus should be considered as a single cardiac-fetal-placental unit. The correlations of systemic vascular resistance, cardiac output, and inotropy index with umbilical artery impedance indicate the key role of these 3 parameters in placental vascular tree development. The umbilical vein flow rate and, therefore, the placental perfusion seems to be influenced not only by these three parameters but also by the maternal cardiovascular kinetic energy.

Maternal hemodynamics for the identification of early fetal growth restriction in normotensive pregnancies.

We aimed at testing systemic vascular resistance (SVR) for the correct identification of early fetal growth restriction (FGR). 61 normotensive patients, gestational age 29 + 0-32 + 0, with suspected diagnosis of early FGR, were submitted to USCOM and to an ultrasound evaluation. 24 patients met the criteria of FGR, and 9 patients developed umbilical artery Doppler alterations. SVR>1006 dyn s·cm-5 correctly identified patients with a subsequent diagnosis of FGR, whereas SVR>1222 dyn s·cm-5 was related to FGR with subsequent umbilical artery Doppler alterations. These data might be important to introduce USCOM in the clinical practice to identify and treat FGR.

Hemodynamic assessment in patients with preterm premature rupture of the membranes (pPROM).

OBJECTIVE: The aim of this study was to assess the hemodynamic differences in women with pPROM versus physiological pregnancies. STUDY DESIGN: This was a prospective case control study of 15 patients with pPROM and 45 controls. Patients and controls were submitted at enrollment to a non-invasive hemodynamic evaluation with UltraSonic Cardiac Output Monitor (USCOM), and to blood tests to check white blood cells count and C-reactive protein (CRP) levels. We followed pPROM patients until delivery noting fetal/neonatal and maternal unfavorable outcomes (maternal fever, APGAR 1' and 5'< 7, stillbirth). RESULTS: Patients with pPROM showed higher values of cardiac output (9.1 ± 2.3 vs 7.1 ± 0.85, p < 0.01), lower systemic vascular resistances (792.1 ± 162 vs 1006.2 ± 110.7, p < 0.01), higher minute distance (32.3 ± 7.8 vs 25 ± 2.8, p < 0.01), lower Potential to Kinetic Energy Ratio (16.5 ± 5.3 vs 22.4 ± 6.8, p < 0.01), higher heart rate (97.5 ± 15.4 vs 82.4 ± 12, p < 0.01) and higher oxygen delivery (1313.2 ± 325.8 vs 1080.7 ± 151.8, p < 0.01) vs. controls. Six out of 15 pPROM patients had an unfavorable outcome. There were no significant differences in CRP levels and WBC count at admission in the two pPROM subgroups, whereas maternal hemodynamics was characterized by lower SVR (718 ± 72 vs 863 ± 123, p = 0.02) in subsequently complicated patients. CONCLUSIONS: Maternal hemodynamics is altered in pPROM patients, with a lower Systemic Vascular Resistance and higher Cardiac Output vs. controls. This hyperdynamic circulation appears to anticipates the changes of serum markers of inflammation (CRP, WBC count) and seems to be more pronounced at admission in pPROM patients developing unfavorable outcomes.

Distinction between SGA and FGR by means of fetal umbilical vein flow and maternal hemodynamics.

OBJECTIVES: To improve identification of fetal growth restriction (FGR) by means of umbilical venous flow (QUV) and maternal hemodynamics, including systemic vascular resistance (SVR) and cardiac output (CO), in order to distinguish between FGR and SGA. METHODS: We enrolled 68 pregnancies (36 SGA, 8 early FGR and 24 late FGR) who underwent a complete fetal hemodynamic examination including QUV and a noninvasive maternal hemodynamics assessment by means of USCOM. RESULTS: In comparison with SGA, QUV and corrected for estimated fetal weight QUV (cQUV) were significantly lower in early and late-FGR. In addition, maternal CO was lower in early and late-FGR, while SVR was lower only in early-onset FGR. According to ROC analysis, cQUV centile (AUC 0.92, 0.72) was the best parameter for the prediction of SGA before and after 32 weeks, followed by SVR and CO. For all parameters, the prediction was always better in the case of early-onset FGR <32 weeks. CONCLUSIONS: UV flow and maternal hemodynamics examination are useful tools to accurately discern between SGA and FGR.