Abnormal maternal cardiac function and morphology in pregnancies complicated by intrauterine fetal growth restriction.

OBJECTIVE: To explore maternal cardiac function through an echocardiographic evaluation, in a group of nulliparous patients with intrauterine fetal growth restriction during the third trimester of pregnancy. METHODS: Twenty-one consecutive nulliparous pregnant women who had fetuses with intrauterine growth restriction (IUGR) and abnormal umbilical artery Doppler pulsatility index (PI) underwent maternal echocardiographic examination during the third trimester of gestation. The data were then compared with those obtained from 21 normal nulliparous women who had fetuses with an estimated fetal weight > 10th percentile and a normal umbilical artery Doppler PI who were considered as the control group. RESULTS: Heart rate was slightly lower in the IUGR group, whereas blood pressure and total vascular resistance were higher compared with the control subjects. End-diastolic volume, stroke volume and cardiac output were lower in the IUGR patients compared with normal patients. The IUGR group had smaller left atrial maximal dimensions and greater left atrial minimal areas compared with the control subjects. Left atrial function was depressed in the IUGR group. A smaller left ventricular mass was present in the IUGR patients compared with the control subjects. Isovolumetric relaxation time (IVRT) was prolonged in the IUGR patients compared with the controls. CONCLUSIONS: The absence of a 'correct' maternal cardiovascular compensatory response to abnormal trophoblastic invasion, might be one of the factors that slowly determine the conditions of reduced placental perfusion and eventually of the development of fetal growth restriction.     

Angiogenic growth factor levels in maternal and fetal blood: correlation with Doppler ultrasound parameters in pregnancies complicated by pre-eclampsia and intrauterine growth restriction.

OBJECTIVES: To correlate levels of angiogenic growth factors with Doppler ultrasound parameters in pregnancies complicated by pre-eclampsia and intrauterine growth restriction (IUGR). METHODS: In 16 women with pre-eclampsia and 15 women with isolated IUGR, pulsatility indices (PI) in the umbilical and uterine arteries were measured by Doppler ultrasonography. At delivery, maternal and fetal blood (umbilical vein and artery separately) was sampled and angiogenic growth factors measured by means of enzyme linked immunosorbent assay (ELISA). RESULTS: Umbilical artery PI was significantly higher in women with IUGR than in those with pre-eclampsia, whereas uterine artery PI was not statistically significantly different. Maternal soluble fms-like tyrosine kinase-1 (sFlt-1) levels were higher in women with pre-eclampsia than in those with IUGR (P < 0.0001). Umbilical vein basic fibroblast growth factor (bFGF) levels were lower in women with pre-eclampsia than in those with IUGR (P < 0.05). Placental growth factor (PlGF) levels in the umbilical vein were below the detection limit in nearly all samples of IUGR fetuses and lower than in those with pre-eclampsia (P < 0.001). Maternal PlGF levels were inversely correlated with PI values of both vessels. In the umbilical vein sFlt-1 was positively and soluble kinase insert domain receptor (sKDR) negatively correlated with umbilical artery PI. No correlation could be found in the serum of the umbilical artery for all growth factors and for vascular endothelial growth factor (VEGF) in all compartments. CONCLUSIONS: The correlations between maternal and fetal angiogenic growth factor serum levels and Doppler ultrasound indices of uterine and umbilical arteries in pre-eclampsia and IUGR reflect the severity of the disorders especially for the fetus. A combination of both measurements may be useful in future screening for early prediction of pregnancy complications. Published by John Wiley & Sons, Ltd.     

Maternal cardiovascular function in pregnancies complicated by intrauterine growth restriction.

OBJECTIVE: To investigate maternal cardiovascular function in pregnancies complicated by intrauterine growth restriction (IUGR). METHODS: Maternal echocardiography and ambulatory blood pressure monitoring were performed in pregnancies complicated by IUGR (n = 12) and controls (n = 12), all of whom were normotensive at enrollment. RESULTS: Compared to controls, maternal blood pressure (P = 0.016) and total vascular resistance (P = 0.008) were higher in IUGR pregnancies. Heart rate was lower (P = 0.003), as was systolic function expressed by midwall fractional shortening (P = 0.04). No significant differences between the two groups were observed for left atrial or left ventricular dimensions, nor for left ventricular geometry. Assessment of diastolic function by means of transmitral Doppler flow measurements revealed a significantly longer isovolumetric relaxation time in pregnancies with IUGR (P = 0.006). CONCLUSIONS: In normotensive pregnancies complicated by IUGR, as compared to controls, there is decreased diastolic and systolic maternal cardiac function, and a higher blood pressure.     

High maternal blood S100B concentrations in pregnancies complicated by intrauterine growth restriction and intraventricular hemorrhage

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with perinatal mortality and with neurologic damage from intraventricular hemorrhage (IVH). We investigated whether S100B, a neural protein found in high concentrations after cell injury in the nervous system, is increased in serum of women whose pregnancies are complicated by IUGR and whose newborns develop IVH. We also explored the prognostic accuracy of maternal serum S100B for IVH in the newborn. METHODS: We conducted a case-control study of 106 pregnancies complicated by IUGR, including a subgroup (n = 26) who developed IVH after birth, and 212 unaffected pregnancies matched for gestational age. Ultrasound examination, Doppler velocimetry patterns (in the utero-placental vessels and middle cerebral artery), and maternal blood collection were performed before birth; cerebral ultrasound and neurologic examinations were performed after birth. RESULTS: S100B was higher (P <0.001) in IUGR pregnancies complicated by IVH than in those that were not and in controls. At a cutoff of 0.72 microg/L, sensitivity was 100% [95% confidence interval (95% CI), 87%-100%] and specificity was 99.3% (97.5%-99.9%) for prediction of IVH (area under the ROC curve, 0.999). The prevalence of IVH was 8.2% in the whole study population, 93% (95% CI, 83.6%-100%) in those with maternal S100B >0.72 microg/L, and 0% (0%-2.5%) in those with maternal S100B <0.72 microg/L. CONCLUSION: For prediction of IVH, measurements of maternal S100B may be useful at times before clinical, laboratory, and ultrasound patterns can identify risk of IVH.     

Polyhydramnios and fetal intrauterine growth restriction: ominous combination.

The purpose of this study was to evaluate the significance of polyhydramnios combined with intrauterine growth restriction. During a 6 year period, 39 fetuses were identified by prenatal sonography as having both polyhydramnios and intrauterine growth restriction. Polyhydramnios was defined as a four-quadrant amniotic fluid index of 24 or greater (mean 30.5, range 24 to 40). Intrauterine growth restriction was defined as estimated fetal weight less than the tenth percentile (Hadlock standards). The mean birth weight was 2213 g. Major anomalies were present postnatally in 92% (36 of 39) of fetuses. Among nine fetuses without sonographically detectable anomalies prenatally, six (67%) proved to have one or more anomalies at birth. Chromosome abnormalities were present in 38% (15 cases) including 10 fetuses with trisomy 18 and one with trisomy 13. The overall mortality rate was 59%. The combination of polyhydramnios and intrauterine growth restriction is ominous. The majority of fetuses have major anomalies or chromosome abnormalities, or both, even when other sonographic abnormalities are absent. Chromosome analysis and detailed fetal evaluation should be offered when polyhydramnios and intrauterine growth restriction are identified prenatally.     

Ultrasound findings in pregnancies complicated by fetal triploidy

Antepartum ultrasound scans of seven pregnancies complicated by fetal triploidy were reviewed. Estimated gestational age (EGA) by ultrasound lagged EGA by last menstrual period in six of seven patients. Normal interval growth of biparietal diameter in the second trimester was demonstrated in all fetuses that had serial scans. Sonographic features commonly associated with fetal triploidy; such as oligohydramnios and cephalocorporal disproportion, were seen in only two cases. Fetal anomalies were evident by ultrasound in five of seven patients. Six of seven patients had partial moles. All of these patients had placentas that appeared abnormal. The ultrasound appearance of the placenta, however, was not the same with each case. Therefore, sonographic features of pregnancies complicated by fetal triploidy are not uniform and the diagnosis cannot be made by ultrasound alone.     

Maternal and fetal hemodynamic effects induced by nitric oxide donors and plasma volume expansion in pregnancies with gestational hypertension complicated by intrauterine growth restriction with absent end-diastolic flow in the umbilical artery.

OBJECTIVE: To evaluate the effect of plasma volume expansion (PVE) and nitric oxide (NO) donors, in addition to antihypertensive therapy for gestational hypertensive pregnancies complicated by intrauterine growth restriction (IUGR) with absent end-diastolic flow (AEDF) in the umbilical artery (UA). METHODS: This was a case-control study into which 32 gestational hypertensive pregnancies with IUGR and AEDF were enrolled. Sixteen of these were treated with antihypertensive drugs, NO donors and PVE (Group A), and 16, matched for maternal age, gestational age and fetal conditions, were treated with antihypertensive drugs only (Group B). All patients underwent fetal and uteroplacental assessment and maternal echocardiography to evaluate total vascular resistance (TVR) and cardiac output before and 5-14 days after initiation of treatment. RESULTS: After 5-14 days of treatment, the maternal TVR in Group A fell from 2170 +/- 248 to 1377 +/- 110 dynes.s.cm(-5) (P < 0.01), and that in Group B fell from 2090 +/- 260 to 1824 +/- 126 dynes.s.cm(-5) (P < 0.01), with the reduction being greater in Group A than in Group B (P < 0.01). There was a significant increase in cardiac output in Group A after 5-14 days of treatment vs. baseline (6.19 +/- 0.77 vs. 4.32 +/- 0.66, P < 0.001), and, after treatment, cardiac output was significantly greater in Group A than it was in Group B (6.19 +/- 0.77 vs. 4.70 +/- 0.44, P < 0.001). Reappearance of end-diastolic flow in the UA occurred in 14/16 patients in Group A but in no patients in Group B (87.5% vs. 0%, P < 0.05). The interval between detection of UA-AEDF and delivery was 28 +/- 16 days in Group A and 11 +/- 6 days in Group B (P < 0.05). CONCLUSION: Administration of NO donors and PVE in gestational hypertensive pregnancies affected by IUGR and UA-AEDF appears to improve both maternal and fetal hemodynamics, inducing prolongation of gestation.     

Early fetal circulation in pregnancies complicated by retroplacental hematoma

The objective of this study was to investigate the effects in early gestation of retroplacental hematomas on Doppler indices measured in different fetal vascular districts and to relate these changes, if any, to the volume of hematoma and pregnancy outcome. Thirty-eight pregnancies complicated by bleeding and ultrasonographic findings of retroplacental hematomas were considered for this study. Menstrual age ranged between 9 and 14 weeks. Blood flow velocity waveforms were measured in the umbilical artery, descending aorta, middle cerebral artery, and inferior vena cava. The pulsatility index in arterial vessels was calculated as well as the percentage reverse flow in the inferior vena cava. The values obtained were compared to previously constructed reference limits. No significant differences were found for any of the Doppler indices when the values obtained in pregnancies complicated by retroplacental hematomas were compared to the reference limits. Furthermore no significant relationships were found between the Doppler indices and either the size of hematoma or pregnancy outcome. In conclusion, retroplacental hematoma does not induce hemodynamic effects in the fetal circulation before 14 weeks, menstrual age. These data do not support the use of Doppler ultrasonography in early gestation for pregnancies complicated by bleeding and retroplacental hematomas. © 1995 John Wiley & Sons, Inc.     

Human fetal cardiovascular profile score and neonatal outcome in intrauterine growth restriction.

OBJECTIVE: To determine whether low cardiovascular profile (CVP) score has prognostic value for predicting neonatal mortality and severe morbidity in human fetuses with growth restriction. METHODS: Seventy-five consecutive growth-restricted fetuses with Doppler examination of cardiovascular hemodynamics within a week prior to delivery comprised the study population. Hydrops, heart size, cardiac function and venous and arterial hemodynamics were evaluated for CVP score. The primary outcome measures were neonatal mortality and cerebral palsy. RESULTS: During the neonatal period, six of 75 neonates died and two had cerebral palsy (Group 1, n = 8). Compared with the fetuses discharged home from hospital (Group 2, n = 67), those in Group 1 were delivered at an earlier gestational age (28 (range, 24-35) weeks vs. 35 (range, 26-40) weeks, P < 0.01) and had lower CVP scores (4 (range, 2-6) vs. 9 (range, 5-10), P < 0.0001). All CVP subscale scores were lower (P < 0.01) in Group 1 than in Group 2 fetuses. Gestational age-adjusted hazard ratios (95% CIs) for adverse neonatal outcome were highest for cardiomegaly (13.9 (1.7-114.3), P = 0.014), monophasic atrioventricular filling pattern or holosystolic tricuspid regurgitation (9.5 (2.3-38.4), P = 0.002) and atrial pulsations in the umbilical vein 7.7 (1.4-41.2), P = 0.017). CONCLUSIONS: Growth-restricted fetuses with adverse neonatal outcome have lower CVP scores than do fetuses with favorable neonatal outcome. The strongest predictors for adverse neonatal outcome in the CVP score were cardiomegaly, abnormal cardiac function with monophasic atrioventricular filling or holosystolic tricuspid regurgitation and increased systemic venous pressure. These assessments have independent prognostic power for adverse neonatal outcome even after adjustment for gestational age.     

An update on maternal cardiac hemodynamics in fetal growth restriction and pre-eclampsia

Pre-eclampsia and fetal growth restriction (FGR) have been long related to primary placental dysfunction, caused by abnormal trophoblast invasion. Nevertheless, emerging evidence has led to a new hypothesis for the origin of pre-eclampsia and FGR. Suboptimal maternal cardiovascular adaptation has been shown to result in uteroplacental hypoperfusion, ultimately leading to placental hypoxic damage with secondary dysfunction. In this review, we summarize current evidence on maternal cardiac hemodynamics in FGR and pre-eclampsia. We also discuss the different approaches for antihypertensive treatment according to the hemodynamic phenotype observed in pre-eclampsia and FGR.     

The efficacy assessment of thigh volume in predicting intrauterine fetal growth restriction by three-dimensional ultrasound

Intrauterine growth restriction (IUGR) is an important issue in perinatology. To assess the efficacy of fetal thigh volume (ThVol) in predicting IUGR, we undertook a prospective cross-sectional study using quantitative 3-D ultrasound (US). During the study period, 30 fetuses with IUGR and 282 fetuses with non-IUGR were included for the ThVol assessment in utero by 3-D US. All the fetuses were singletons and had follow-up to the delivery to determine whether they were complicated with IUGR or not. Our results showed fetal ThVol assessed by 3-D US can differentiate fetuses with IUGR from fetuses with non-IUGR well. Using the 10th percentile as the screening threshold, the sensitivity of fetal ThVol in predicting IUGR was 86.6%, with specificity 91.1%, predictive value of positive test 51.0%, predictive value of negative test 98.5% and accuracy 90.7%. In conclusion, fetal ThVol assessed by quantitative 3-D US can be used to predict fetuses with IUGR antenatally. We believe fetal ThVol assessment by 3-D US would be a useful test in detecting fetuses with IUGR.     

胎儿生长受限孕妇血及脐血内脂过氧化物和一氧化氮水平

目的探讨母血及脐血中脂质过氧化物（LPO）和一氧化氮（NO）水平与胎儿生长受限（FGR）发生的关系及其临床应用价值。方法取38例妊娠合并FGR（FGR组）及50名正常孕妇（对照组）肘静脉血及其新生儿脐血,应用改良的硫代巴比妥酸（TBA）法测定血清LPO水平;应用硝酸盐还原酶法测定血清NO水平。结果FGR组患者血LPO和NO水平与对照组相比均显著升高（P〈0．01）,其新生儿脐血LPO和NO水平也显著升高（P〈0．001）。两组孕妇母血、脐血中LPO和NO水平均呈正相关（P均〈0．01）。结论LPO和NO均可能参与了FGR的发病,检测母血及脐血中LPO和NO水平可作为FGR的辅助诊断指标之一。     

胎儿生长受限孕妇血及脐血内脂质过氧化物和一氧化氮水平

目的探讨母血及脐血中脂质过氧化物(LPO)和一氧化氮(NO)水平与胎儿生长受限(FGR)发生的关系及其临床应用价值。方法取38例妊娠合并FGR(FGR组)及50名正常孕妇(对照组)肘静脉血及其新生儿脐血,应用改良的硫代巴比妥酸(TBA)法测定血清LPO水平;应用硝酸盐还原酶法测定血清NO水平。结果FGR组患者血LPO和NO水平与对照组相比均显著升高(P<0.01),其新生儿脐血LPO和NO水平也显著升高(P<0.001)。两组孕妇母血、脐血中LPO和NO水平均呈正相关(P均<0.01)。结论LPO和NO均可能参与了FGR的发病,检测母血及脐血中LPO和NO水平可作为FGR的辅助诊断指标之一。     

Current concepts in intrauterine growth restriction

Regulation of fetal growth is multifactorial and complex. Diverse factors, including intrinsic fetal conditions as well as maternal and environmental factors, can lead to intrauterine growth restriction (IUGR). The interaction of these factors governs the partitioning of nutrients and rate of fetal cellular proliferation and maturation. Although IUGR is probably a physiologic adaptive response to various stimuli, it is associated with distinct short- and long-term morbidities. Immediate morbidities include those associated with prematurity and inadequate nutrient reserve, while childhood morbidities relate to impaired maturation and disrupted organ development. Potential long-term effects of IUGR are debated and explained by the fetal programming hypothesis. In formulating a comprehensive approach to the management and follow-up of the growth-restricted fetus and infant, physicians should take into consideration the etiology, timing, and severity of IUGR. In addition, they should be cognizant of the immediate perinatal response of the growth-restricted infant as well as the childhood and long-term associated morbidities. A multi disciplinary approach is imperative, including early recognition and obstetrical management of IUGR, assessment of the growth-restricted newborn in the delivery room, possible monitoring in the neonatal intensive care unit, and appropriate pediatric follow-up. Future research is necessary to establish effective preventive, diagnostic, and therapeutic strategies for IUGR, perhaps affecting the health of future generations.     

Association of maternal and/or fetal factor V Leiden and G20210A prothrombin mutation with HELLP syndrome and intrauterine growth restriction

This study was conducted to investigate the association of maternal and/or fetal factor V Leiden (FVL) and G20210A prothrombin mutation with HELLP syndrome. FVL and G20210A prothrombin mutation were determined using PCR. Sixty-three pregnant women, 36 of them diagnosed with HELLP syndrome, were included in the study. Overall, 68 children were born as a result of these pregnancies and blood sampling was possible in 28 out of 39 children from HELLP patients and 25 out of 29 children from the control women. The prevalence of a maternal FVL was elevated 2-fold in HELLP patients compared with the control women [six out of 36 (16.7%) compared with two out of 27 (7.4%); P =0.282]. None of the HELLP patients and only one woman in the control group was found to be positive for the G20210A prothrombin mutation (P =0.251). The fetal carrier frequency was four out of 28 compared with three out of 25 for FVL (P =0.811), and two out of 28 compared with one out of 25 for G20210A prothrombin mutation (P =0.629). Intrauterine growth restriction (IUGR) was significantly higher in fetuses found to be positive for a thrombophilic mutation (P =0.022). IUGR occurred in seven out of ten fetuses with a thrombophilic mutation compared with 11 out of 43 in fetuses without a mutation. The prevalence of FVL, but not of the G20210A prothrombin mutation, seems to be elevated in women with HELLP syndrome. A fetal thrombophilic mutation does not contribute significantly to the clinical features of the HELLP syndrome. Our results demonstrate a fetal contribution to IUGR. Fetal thrombophilic mutations may lead to placental microthrombosis, which consecutively could lead to a disturbed fetoplacental blood flow and thus cause growth restriction.     

Upregulation of ENDOU in cytotrophoblasts from placenta complicated with preeclampsia and fetal growth restriction

Placental hypoplasia is associated with the pathophysiology of fetal growth restriction and preeclampsia. The placenta consists of differentiated trophoblasts, including cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts. Cytotrophoblasts are thought to have stem-like characteristics and the ability to differentiate into syncytiotrophoblasts and extravillous trophoblasts. However, it is poorly understood whether isolated cytotrophoblasts derived from hypoplastic placentas have specific features compared with those in normal placentas. This study aimed to determine the features of cytotrophoblasts in hypoplastic placentas. Differentially expressed proteins between isolated cytotrophoblasts from hypoplastic placenta with fetal growth restriction and those from the normal placenta were determined by liquid chromatography-tandem mass spectrometry. Among 6,802 proteins, 1,253 and 2,129 proteins were more than 2-fold upregulated and downregulated, respectively. Among them, ENDOU (endonuclease, poly(U) specific), which has high homology with the coronavirus endoribonuclease nonstructural protein 15 (Nsp15), showed a significantly increased expression in cytotrophoblasts from the placenta with fetal growth restriction related to preeclampsia compared with those in normal control placenta. These results provide insight into the pathological mechanisms of placental hypoplasia and additional information on preeclamptic symptoms in cases of SARS-CoV-2 infected placenta, although further investigation is needed.