Fetal corticotrophin-releasing hormone mRNA, but not phosphatidylserine-exposing microparticles, in maternal plasma are associated with factor VII activity in pre-eclampsia

Summary.  Background:  Pre-eclampsia is associated with increased placental debris circulating in maternal plasma. Objectives:  This study related placental debris to maternal markers of coagulation and endothelial activation in pre-eclampsia. Patients/methods:  Circulating fetal corticotrophin-releasing hormone (CRH) mRNA and phosphatidylserine (PS)-exposing microparticles were assayed in third trimester plasma from women with pre-eclampsia ( n  = 32) and controls ( n  = 32) matched for age, body mass index, parity, and gestational age at sampling. Markers of maternal hemostasis and endothelial function were assessed. Results:  Fetal CRH mRNA levels were higher in pre-eclampsia [mean 0.75 (SD 2.77) CRH/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio] than in control pregnancies [0.20 (0.74), P  = 0.014]. PS-exposing microparticle levels were not different between the groups. Women with pre-eclampsia had higher levels of tissue factor pathway inhibitor (TFPI), prothrombin F ₁₊₂ fragment ( F ₁₊₂), factor XIIa, soluble vascular cell adhesion molecule 1, von Willebrand factor and plasminogen activator inhibitor 1 than controls. Fetal CRH mRNA correlated with TFPI in pre-eclampsia and control groups ( r  = 0.38, P  = 0.031, and r  = 0.37, P  = 0.039, respectively). Fetal CRH mRNA correlated with FVII activity ( r  = 0.43, P  = 0.017) and PS-exposing microparticles correlated inversely with F ₁₊₂ ( r  = −0.64, P  < 0.001) in pre-eclampsia. Conclusions:  Placental debris, assessed by fetal CRH mRNA levels in maternal blood, is related to coagulation potential, i.e. FVII activity, but not to markers of coagulation or endothelial activation in pre-eclampsia.     

Nitric oxide donors in pregnancy: fetomaternal hemodynamic effects induced in mild pre-eclampsia and threatened preterm labor.

OBJECTIVE: The present study was performed to determine whether there are significant differences in the effects of the nitric oxide donor, glyceryl trinitrate, administration in pregnancies complicated by mild pre-eclampsia compared to the effects in pregnancies which are uncomplicated by this pathology. Glyceryl trinitrate is able to release nitric oxide (NO); deficiency of NO has been hypothesized in the pathogenesis of pre-eclamptic disorders. METHODS: In this prospective study, ten patients with threatened preterm labor and ten patients with mild preeclampsia were studied at around 30 weeks of pregnancy. The maternal blood pressure, maternal heart rate, fetal heart rate and flow velocity waveforms of the placental uterine artery, umbilical artery and fetal middle cerebral artery, evaluated by means of color Doppler and pulsed Doppler, were recorded before and 10, 20 and 30 min after the sublingual administration of 0.3 mg of glyceryl trinitrate or placebo. The pulsatility index (PI) was calculated. The percentage change from the control period (delta %) was calculated for each parameter at 10, 20 and 30 min. Ten normal pregnant women at the same gestational age were used as controls and were administered a placebo. RESULTS: The maternal blood pressure recorded as systolic and diastolic values, demonstrated a significant decrease in the pre-eclampsia group after glyceryl trinitrate administration; the delta % at any time considered was significantly higher in the pre-eclampsia group than in the threatened preterm labor group. The PI of the placental uterine artery showed a significant decrease in both groups after 20 and 30 min from drug administration; the delta % at 20 and 30 min was significantly higher in the pre-eclampsia group than in the threatened preterm labor group. The PI of the umbilical artery showed a significant decrease after 30 min from the glyceryl trinitrate administration. The fetal heart rate showed no significant variations during the study in either group. The PI of the fetal middle cerebral artery showed no significant variations during the study in either group. No parameter was changed in the control group. CONCLUSION: Glyceryl trinitrate administration was followed by a greater reduction of the resistance to blood flow in the fetoplacental circulation of the pregnancies affected by mild pre-eclampsia compared to pregnancies uncomplicated by this pathology. This effect can be attributed to the NO released by the drug which offsets the decreased production of NO, postulated to contribute to the pathogenesis of pre-eclampsia.     

N-terminal pro-C-type natriuretic peptide, but not C-type natriuretic peptide, is greatly elevated in the fetal circulation

We have identified recently a new peptide, NT-proCNP(1-50) (N-terminal pro-C-type natriuretic peptide), in the circulation of humans and sheep. A previous report of an elevated fetal-maternal gradient in immunoreactive CNP raised the possibility that processing and metabolism of proCNP may differ in maternal and fetal tissues. We therefore collected matching peripheral maternal and umbilical cord plasma samples at delivery from women with normotensive and pre-eclamptic pregnancies to investigate the presence and concentrations of CNP and NT-proCNP using HPLC and RIA. Plasma concentrations of NT-proCNP in normotensive umbilical cord plasma were 10-fold higher than maternal venous levels (246+/-17 compared with 24.3+/-1.8 pmol/l; P <0.001) and much higher than corresponding levels of CNP (3.6+/-0.4 compared with 1.8+/-0.3 pmol/l in the fetal and maternal plasma respectively; P <0.001). Although there was no significant difference between normotensive and pre-eclamptic plasma CNP concentrations in either maternal or umbilical cord blood, NT-proCNP showed a significant statistical interaction ( F =5.8, P =0.025) between the source (maternal or fetal) and gestational group (normotensive or pre-eclamptic). Maternal NT-proCNP levels were raised in the pre-eclampsia group, whereas the converse was observed in umbilical cord blood. In conclusion, the greatly elevated ratio of NT-proCNP/CNP in fetal compared with maternal plasma suggests that synthesis, as well as clearance, of CNP (but not NT-proCNP clearance) are markedly increased in fetal tissues.     

胰岛素样生长因子-Ⅰ、Ⅱ水平与子癎前期相关性研究

目的：探讨胰岛素样生长因子Ⅰ、Ⅱ水平在子癎前期发病机制及诊断中的作用。方法：选择38例子癎前期孕妇为子癎前期组（其中轻度18例,重度20例）,30例正常妊娠晚期孕妇为对照组,应用ELISA检测对照组和轻、重度子癎前期组孕妇静脉血、新生儿脐血及羊水中胰岛素样生长因子-Ⅰ、Ⅱ的含量,分析与子癎前期发病相关性。结果：（1）孕妇血、新生儿脐血及羊水中胰岛素样生长因子 含量在重度子癎前期组明显低于轻度子癎前期组（P〈0．01）,轻度子癎前期组明显低于对照组（P〈0．01）。（2）孕妇血及羊水中胰岛素样生长因子Ⅱ含量在重度子癎前期组明显低于轻度子癎前期组（P〈0．01）,轻度子癎前期组明显低于对照组（P〈0．01）;新生儿脐血中胰岛素样生长因子-Ⅱ含量在重度子痢前期组明显高于轻度子癎前期组（P〈0．01）,轻度子癎前期组明显高于对照组（P〈0．01）。（3）子痢前期孕妇血及羊水中胰岛素样生长因子-Ⅰ、Ⅱ的水平与病情轻重呈正相关,新生儿脐血,胰岛素样生长因子-Ⅰ水平与病情轻重呈正相关,胰岛素样生长因子-Ⅱ水平与病情轻重呈负相关。结论：孕妇血、新生儿脐血及羊水中胰岛素样生长因子-Ⅰ、Ⅱ水平变化可作为预测和诊断子癎前期发病和疾病程度的一个指标。     

Precursors to pre-eclampsia: are there markers in the fetal circulation?

One of the fundamental issues in pre-eclampsia (hypertension in pregnancy) research is to find serum proteins that can act as markers of disease predisposition, remote disease onset, imminent disease onset or disease activity at the height of its destructive powers. We make assumptions, not infrequently, that positive findings at the time of delivery reflect early changes in the maternal and fetal circulations. Very little has been defined in terms of fetal circulation, as it is, by and large, deemed to be harder to access and less likely to lend itself to useful non-invasive diagnostic tests in early pregnancy. The study published in this issue of Clinical Science by Prickett et al. shows that there is a differential expression of the precursor molecule of CNP (C-type natriuretic peptide), N-terminal proCNP, in pre-eclampsia. At term, pre-eclamptic umbilical cord plasma concentrations are decreased relative to normal pregnancy, possibly reflecting a decrease in placental production. At the same time maternal levels are increased relative to normal pregnancies and this possibly reflects an increase in myometrial/endovascular production. There is no doubt that the predominant actions of these hormones are local and whether plasma levels are a true reflection of dynamic changes in local production and effect is yet to be seen. This study represents a promising start in identifying large stable molecules which could be markers for pre-eclampsia. This study has relatively small numbers of patients and work still needs to be done to determine the utility of umbilical cord levels in early phases of the disease. Whether serum levels of N-terminal proCNP can provide an accurate reflection of normal or pathological maternal uterine adaptation to pregnancy remains a question worth evaluating.     

Increased uterine artery vascular impedance is related to adverse outcome of pregnancy but is present in only one-third of late third-trimester pre-eclamptic women.

OBJECTIVE: Signs of increased uterine artery vascular impedance in mid-gestation are strongly related to pre-eclampsia later in pregnancy. Whether this is true for the late third trimester is, however, unclear. The aim of the present study was to analyze the frequency of increased uterine artery vascular impedance in the third trimester, and its relationship to abnormal umbilical artery Doppler and adverse outcome of pregnancy. METHODS: This was a retrospective study of uterine and umbilical artery Doppler velocimetry in 570 pregnancies complicated by pre-eclampsia. The managing clinician was informed only about the umbilical artery flow. The Doppler recordings were related to severity of pre-eclampsia, prematurity, fetal growth restriction, and rates of Cesarean section and admission to neonatal intensive care. RESULTS: Increased umbilical artery vascular impedance was seen in 59 cases (10.4%), seven having absent or reversed end-diastolic flow. Uterine artery notching was seen in 145 cases (25%), 88 (15%) having bilateral notches. Either increased uterine artery pulsatility index (PI) or notching, or both, were seen in 207 women (36.3%). In 108 women with severe pre-eclampsia, 38 (35.2%) had uterine artery notching. Signs of increased uteroplacental vascular impedance were more common in severe than in mild pre-eclampsia (57.4% vs. 31.4%), in premature than in term pregnancies (70.9% vs. 28.4%), and were more prevalent than abnormality in the umbilical artery (36.3% vs. 10.4%). CONCLUSION: Only one-third of pre-eclamptic cases showed signs of increased uterine artery vascular impedance in the third trimester. However, signs of increased vascular impedance were much more frequent in the uterine than in the umbilical arteries and were strongly related to adverse outcome of pregnancy.     

Doppler velocimetry and the assessment of fetal well-being in normal and diabetic pregnancies.

Doppler ultrasound has been proposed as a useful addition to antepartum testing in high-risk pregnancies. Increased placental resistance has been associated with underlying placental vascular disease, as well as abnormal fetoplacental blood flow. Since pregnancies complicated by diabetes are at risk for these complications, the application of Doppler ultrasonography for such pregnancies has been evaluated by several investigators.Multiple investigations have examined the relationship between maternal blood glucose levels and abnormal Doppler waveforms in women with diabetes. Of the nine published studies, four found a correlation between Doppler indices and glucose control, as measured by mean blood glucose levels and glycosylated hemoglobin levels, while five did not. However, this apparent discrepancy may be explained by the fact that the majority of women studied were in good or excellent control, as this is currently the accepted standard of care. In fact, the one study performed in primarily non-diabetic women demonstrated that increases in maternal plasma glucose concentrations of 30 mg/dl were followed by significant rises in the mean pulsatility index in both the umbilical and carotid arteries. More dramatic was the finding by most investigators that systolic/diastolic (S/D) ratios in third-trimester umbilical arteries were elevated in women with evidence of diabetic microvascular disease. Elevated third-trimester S/D ratios were associated with adverse maternal and perinatal outcomes in these women, specifically pre-eclampsia and intrauterine growth retardation.In conclusion, although elevated Doppler indices correlated with adverse outcomes in diabetic pregnancies, Doppler indices may be elevated in the otherwise uncomplicated diabetic patient with associated microvascular disease and with a normal outcome. Therefore, the Doppler ultrasound assessment of fetal well-being in diabetic pregnancies must be interpreted with caution.     

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.     

Circulating levels of adiponectin and leptin at 23-25 weeks of pregnancy in women with impaired placentation and in those with established fetal growth restriction

Adiponectin and leptin, two adipose-tissue-derived proteins, have been reported to be elevated in women with established PE (pre-eclampsia). The aim of the present study was to investigate whether alterations in adiponectin and leptin levels predate the development of PE and FGR (fetal growth restriction) in women at increased risk of these complications, as assessed by Doppler examination of the uterine arteries during the second trimester of pregnancy. We also sought to investigate the circulating levels of adiponectin and leptin in women with established severe early-onset FGR. The study included three groups of pregnant women at 23-25 weeks: Group A (n=44) with normal uterine artery Doppler waveforms, Group B (n=49) with abnormal Doppler waveforms and normal fetal growth at the time of the examination, and Group C (n=15) with established severe FGR and abnormal Doppler waveforms. All women had plasma adiponectin and leptin measured by sensitive immunoassays. In Group B, 19 women had a normal outcome, 17 delivered infants with FGR and 13 developed PE. The women who developed PE delivered smaller babies earlier than women with a normal outcome (P<0.001). There were no significant differences in adiponectin levels between any of the groups (overall P=0.3). Leptin concentrations, expressed as MoM (multiples of the median) of Group A, were higher in women in Group C, i.e. established severe FGR at 2.5 (1.2-2.7) MoMs (overall P<0.001), compared with all of the other groups and subgroups. In conclusion, we found that, in pregnancies complicated by severe early-onset FGR, the maternal plasma concentration of leptin is twice as high as in normal pregnancies. However, the second trimester levels of maternal plasma adiponectin and leptin in pregnancies that subsequently develop PE and/or FGR are not significantly different from normal and, consequently, it is unlikely that these markers will be useful as predictors of these pregnancy complications.     

Fetal middle cerebral to uterine artery pulsatility index ratios in normal and pre-eclamptic pregnancies.

OBJECTIVES: To calculate the normal range for the fetal middle cerebral artery (MCA)/uterine artery pulsatility index (PI) ratio in the third trimester of pregnancy and to assess its value, compared with that of the MCA/umbilical artery PI ratio, in predicting an unfavorable outcome of pregnancies complicated by pre-eclampsia. METHODS: Doppler blood flow velocimetry of the uterine and umbilical arteries and fetal MCA was performed. We calculated the ratios between 1) the PI of the MCA and the mean PI value of both uterine arteries and 2) the PI of the MCA and the PI of the umbilical artery. All women were examined at or beyond 26 weeks of gestation. A cross-sectional study of 231 normal pregnancies was conducted to construct the reference range. Values below the 5th percentile or an MCA/umbilical artery PI ratio lower than 1.08 were defined as brain-sparing. A further 115 pregnancies with pre-eclampsia (50 mild and 65 severe) were assessed prospectively and the results were related to perinatal outcome. The accuracy of MCA/uterine artery and MCA/umbilical artery PI ratios for prediction of unfavorable pregnancy outcome was compared. RESULTS: Normal MCA/uterine artery PI ratios decreased with advancing gestational age. Redistribution of the fetal circulation indicated by a low MCA/uterine artery PI ratio was seen in 30% of the mild (n=15) and 46% of the severe (n=30) pre-eclamptic cases. There was a significant difference between those without and those with signs of brain-sparing, respectively, in mean birth weight (2456.0 vs. 1424.5 g), gestational age at delivery (35.6 vs. 31.3 weeks) and gestational age at the time of examination (34.9 vs. 30.9 weeks). Furthermore, there was a significantly higher rate of small-for-gestational-age (SGA) neonates (57.8% vs. 25.7%), preterm delivery (100% vs. 81.8%) and Cesarean section (90.7% vs. 66.7%) in cases with an MCA/uterine artery PI ratio below the 5th percentile. However, there was no difference between the groups in the rate of low 5-min Apgar scores, admission to the neonatal intensive care unit, or deliveries before 34 weeks. The MCA/uterine artery and MCA/umbilical artery PI ratios were similar in the prediction of adverse perinatal outcome. Both ratios were better at predicting the outcome of pregnancy than were signs of increased vascular impedance in either the umbilical or uterine arteries. CONCLUSIONS: Normal MCA/uterine artery PI ratio decreases with gestational age. Abnormally low MCA/ uterine artery PI ratios are related to unfavorable pregnancy outcome. The predictive value of the MCA/uterine artery PI ratio is similar to that of the MCA/umbilical artery PI ratio.     

Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction

The present study was performed to compare serum concentrations of maternal and fetal angiogenic growth factors in IUGR (intrauterine growth restriction) and normal pregnancy at the time of delivery. VEGF (vascular endothelial growth factor), PlGF (placental growth factor), sFlt-1 (soluble fms-like tyrosine kinase 1), sKDR (soluble kinase domain receptor) and bFGF (basic fibroblast growth factor) were measured by ELISA in serum from a maternal peripheral vein, the umbilical vein and the umbilical arteries in 15 women with pregnancies complicated by IUGR and 16 controls (women with normal pregnancies). In IUGR, sFlt-1 was increased, and PlGF and sKDR were decreased, in both maternal serum and serum from the umbilical vein. Additionally, bFGF was increased in serum from the umbilical vein of women with pregnancies complicated by IUGR. No significant differences in growth factor concentrations between the groups were found in serum from the umbilical artery. In both groups, levels of VEGF were higher and levels of sFlt-1 were lower in serum from the umbilical vein and umbilical artery compared with maternal serum. PlGF levels were found to be lower in serum from the umbilical vein compared with maternal serum in both groups, whereas PlGF levels in serum from the umbilical artery were significantly lower only in the control group. These findings suggest an imbalance of angiogenic and anti-angiogenic factors in IUGR, with formation of an anti-angiogenic state in maternal and, to a lesser extent, umbilical vein blood. The placenta appears to play a central role in the release of sFlt-1 into maternal and umbilical blood. Umbilical artery blood was unaffected in IUGR, indicating that the fetus does not contribute to changes in angiogenic growth factor concentrations.     

Power spectrum analysis of heart rate and blood flow velocity variability measured in the umbilical and uterine arteries in early pregnancy: a comparative study.

OBJECTIVE: To compare power spectral derived variability parameters from the fetal side of the placental circulation with those from the maternal side of the placental circulation, during early pregnancy. METHODS: Doppler velocity waveforms were obtained from both the umbilical and the uterine arteries in a study group of 40 pregnant women between 10 and 14 (n = 25) and 15 and 20 (n = 15) weeks of gestation. The coefficient of variation of both the beat-to-beat heart rate variability and the blood flow velocity variability was determined. The ratio of the integrated low-frequency components (< 0.2 Hz) and the integrated high-frequency components (> 0.2 Hz) from normalized power spectrum analysis (LH-ratio) was established, to reflect sympathovagal balance. RESULTS: The coefficient of variation and LH-ratio of fetal heart rate variability constitute only a fraction of the same maternal heart rate variability parameters. Nevertheless a highly significant increase (P < 0.001) in LH-ratio was demonstrated with advancing gestational age. The coefficient of variation and LH-ratio of blood flow velocity variability were significantly lower in the fetal umbilical artery only in the 10-14-weeks' gestation group. Due to a decrease of the maternal uterine blood flow velocity variability parameters with advancing gestational age, statistically equal fetal and maternal values for coefficient of variation and LH-ratio were found in the 15-20 weeks' gestation group. CONCLUSIONS: The increase in LH-ratio of fetal heart rate variability indicates functional development of the fetal autonomic nervous system at 15-20 weeks' gestation. The umbilical blood flow velocity variability may be secondary to maternal uterine arterial flow variability rather than due to primary changes in fetal cardiovascular function.     

Effects of antenatal betamethasone on maternal and fetoplacental matrix metalloproteinases 2 and 9 activities in human singleton pregnancies.

BACKGROUND: A single course of antenatal betamethasone is administered to women at risk of preterm labor to advance fetal lung maturation. Matrix metalloproteinases (MMPs) are collagen-degrading enzymes that remodel extracellular matrix components during lung development. We tested the hypothesis that the effects of betamethasone on fetal lung maturation involve changes in MMP activity. METHODS: We conducted a prospective, observational pilot study of three groups of singleton pregnancies. Group 1 (n = 21) was composed of women who were antenatally treated with a single course of betamethasone and who delivered < 37 weeks of gestation, group 2 (n = 7) was composed of matched untreated women who delivered < 37 weeks of gestation, and group 3 (n = 15) was composed of untreated women who delivered > 37 weeks of gestation. Maternal blood, mixed cord blood, and placental samples were collected at the time of delivery for MMP-2 and MMP-9 activity and tissue inhibitor of metalloproteinases (TIMP)-1 and -2 levels. RESULTS: MMP-2 activity was significantly higher in the maternal, placental, and fetal compartments in group 1 compared with group 2 (p < .05). TIMP-2 levels were lower in groups 1 and 2 compared with group 3. Maternal TIMP-2 levels were higher (p < 0.003), whereas fetal TIMP-1 (p < .01) and MMP-9 to TIMP-1 ratios (p < .05) were lower when delivery was delayed more than 2 weeks following betamethasone treatment. CONCLUSION: We conclude that elevated MMP-2 activity in the maternal and fetoplacental compartments may suggest a mechanism, in part, for betamethasone-induced fetal lung maturation.     

Maternal hyperoxygenation: a fetal blood flow velocity prognosis test in small-for-gestational-age fetuses?

Maternal hyperoxygenation tests were performed in 20 small-for-gestational age fetuses using 8 l/min of 70% humidified oxygen given for 20 min through a face mask.Assessments were made of the fetal blood flow velocity, and the placental resistance index, cerebral resistance index and cerebroplacental ratio were calculated in 78 normal pregnancies and in the 20 small-for-gestational-age fetuses during the hyperoxygenation test. The test was positive when the velocity indices increased by more than 10%. The reference ranges for placental and cerebral resistance indices were derived from the data measured in the 78 normal pregnancies. Of the 20 small-for-gestational-age fetuses, three had a normal placental resistance index with a negative oxygen test response and a good fetal outcome. Seven had a mild increase in placental resistance index (> +2SD) and a brain-sparing effect was observed (cerebral resistance index < -2SD or cerebroplacental ratio < l). In these seven fetuses, the fetal outcome was not poor, whether the oxygen test response was negative or positive.Ten of the 20 small-for-gestational-age fetuses had no umbilical diastolic flow (placental resistance index = 1) and a brain-sparing effect. Their outcome was strongly dependent on the oxygen test response: a positive response indicated a good prognosis, a negative one a poor fetal outcome.     

Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler and PAPP-A at 11-14 weeks' gestation.

OBJECTIVE: To assess the role of maternal demographic characteristics, uterine artery Doppler velocimetry, maternal serum pregnancy-associated plasma protein-A (PAPP-A) and their combination in screening for pre-eclampsia and small-for-gestational age (SGA) fetuses at 11-14 weeks. METHODS: This was a prospective study of 878 consecutive women presenting for a routine prenatal ultrasound examination at 11-14 weeks. Pulsed wave Doppler was then used to obtain uterine artery flow velocity waveforms and the mean pulsatility index (PI) of the uterine arteries was calculated. Maternal serum samples for PAPP-A were assayed. Along with maternal history, these measurements were compared in their ability to predict adverse outcome, defined as pre-eclampsia and/or SGA and/or placental abruption. RESULTS: Mean uterine artery PI > or = 95(th) centile and PAPP-A < or = 10(th) centile each predicted 23% of the women that developed pre-eclampsia and 43% of cases of placental abruption. For SGA < or = 5(th) centile, mean uterine artery PI > or = 95(th) centile predicted 23% of cases and PAPP-A < or = 10(th) centile predicted 34%. Independent predictors for subsequent development of pre-eclampsia were increased mean uterine artery PI > or = 95(th) centile (OR, 2.76; 95% CI, 1.11-6.81) and maternal history of pre-eclampsia/hypertension (OR, 50.54; 95% CI, 10.52-242.73). The predicting factors for SGA < or = 5(th) centile were increased mean uterine artery PI > or = 95(th) centile (OR, 2.0; 95% CI, 1.07-3.74) and low PAPP-A (OR, 0.43; 95% CI, 0.20-0.93). Increased uterine artery PI was the only independent factor in the prediction of placental abruption (OR, 8.49; 95% CI, 2.78-25.94). The combination of uterine artery PI and maternal history of pre-eclampsia/hypertension was better than was using uterine artery Doppler alone in predicting pre-eclampsia. Similarly, for the prediction of SGA < or = 5(th) centile, combining uterine artery Doppler and maternal serum PAPP-A was better than was uterine artery Doppler alone. In both cases, the difference approached statistical significance. CONCLUSIONS: The combination of maternal history with abnormal uterine artery Doppler and low PAPP-A level at 11-14 weeks achieves better results than does either test alone in the prediction of pre-eclampsia and SGA.     

Monoamine-oxidizing enzymes in human pregnancy

The activity of benzylamine oxidase (BzAO) was investigated in human maternal blood at all stages of gestation, including parturition, as well as in the puerperium. In addition, BzAO and monoamine oxidase (MAO) A and B activities were assayed in amniotic fluid, placenta, placental vessels and umbilical vessels. No correlation was found between BzAO values in maternal blood and fetal growth. Highly significant variations in maternal plasma BzAO activity were seen by the end of the first trimester, at parturition and at 6–72 h post-partum.

The predominance of MAO A in placenta was again confirmed, whereas in vascular tissue and amniotic fluid, BzAO was clearly preponderant; in the latter, no MAO A activity could be detected. Placental vessels showed significantly higher MAO A activity than umbilical vessels. BzAO and what appears to be a true, soluble MAO B were demonstrated in amniotic fluid.

The physiological implications of these findings are discussed.     

Chronic hypertension in pregnancy.

Pregnancies in women with chronic hypertension are at increased risk of superimposed pre-eclampsia, abruptio placentae, fetal growth retardation and prematurity. The frequencies of these complications are increased in those women who have high-risk chronic hypertension, ie severe hypertension or pre-existing cardiovascular or renal diseases, as well as in those with target organ damage. Such women should receive antihypertensive therapy and close management to improve maternal and fetal outcome. In women with low-risk chronic hypertension, antihypertensive treatments do not improve pregnancy outcome. Prophylactic low-dose acetylsalicylic acid treatment does not reduce the frequency of superimposed pre-eclampsia nor does it improve perinatal outcome in these pregnancies.     

Chronic hypertension in pregnancy

Pregnancies in women with chronic hypertension are at increased risk of superimposed pre-eclampsia, abruptio placentae, fetal growth retardation and prematurity. The frequencies of these complications are increased in those women who have high-risk chronic hypertension, ie severe hypertension or pre-existing cardiovascular or renal diseases, as well as in those with target organ damage. Such women should receive antihypertensive therapy and close management to improve maternal and fetal outcome. In women with low-risk chronic hypertension, antihypertensive treatments do not improve pregnancy outcome. Prophylactic low-dose acetylsalicylic acid treatment does not reduce the frequency of superimposed pre-eclampsia nor does it improve perinatal outcome in these pregnancies.     

Comparison between three-dimensional placental volume at 12 weeks and uterine artery impedance/notching at 22 weeks in screening for pregnancy-induced hypertension, pre-eclampsia and fetal growth restriction in a low-risk population.

OBJECTIVES: To compare the value of three-dimensional placental volume at 12 weeks and uterine artery Doppler at 22 weeks for predicting pregnancy-induced hypertension (PIH), pre-eclampsia and fetal growth restriction in a low-risk population. METHODS: Over a 20-month period we calculated the placental quotient (PQ = placental volume/crown-rump length) at 11-13 weeks' gestation in all women with singleton pregnancies who booked for delivery in our hospital. At 22 weeks, in the same population, we calculated the mean pulsatility index (PI) of both uterine arteries and the presence of an early diastolic notch was noted. Logistic regression models, the PQ and Doppler parameters were used to compare the two screening methods for subgroups of pregnancy outcome. RESULTS: Complete outcome data were obtained in 2489 consecutive singleton pregnancies. Logistic regression models for the detection of pre-eclampsia had a sensitivity of 38.5% (PQ) vs. 44.8% (Doppler); for the detection of small-for-gestational age (SGA) the sensitivity was 27.1% (PQ) vs. 28.1% (Doppler) at a specificity of 90%. Taking a PQ of or= 90th centile and a bilateral notch, the sensitivity for detection of SGA was 25.0%, 20.2% and 22.0%, respectively; for PIH it was 9.5%, 4.8% and 4.8%; for pre-eclampsia without SGA it was 20.0%, 28%, 12%; for PIH/pre-eclampsia with SGA it was 30.8%, 46.1% and 69.2%. In the group with the most severe complications, in which delivery took place before 34 weeks, the sensitivity was 50.0%, 50.0% and 38.9%, respectively. CONCLUSIONS: PQ at 12 weeks and uterine artery Doppler at 22 weeks have similar sensitivities for predicting pre-eclampsia and fetal growth restriction, although uterine artery Doppler is marginally more sensitive for the prediction of pre-eclampsia. While both methods are insufficient for screening in a low-risk population, the PQ method has the potential advantage of being performed in the first trimester.     

Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches

Adverse influences during fetal life alter the structure and function of distinct cells, organ systems or homoeostatic pathways, thereby 'programming' the individual for an increased risk of developing cardiovascular disease and diabetes in adult life. Fetal programming can be caused by a number of different perturbations in the maternal compartment, such as altered maternal nutrition and reduced utero-placental blood flow; however, the underlying mechanisms remain to be fully established. Perturbations in the maternal environment must be transmitted across the placenta in order to affect the fetus. Here, we review recent insights into how the placenta responds to changes in the maternal environment and discuss possible mechanisms by which the placenta mediates fetal programming. In IUGR (intrauterine growth restriction) pregnancies, the increased placental vascular resistance subjects the fetal heart to increased work load, representing a possible direct link between altered placental structure and fetal programming of cardiovascular disease. A decreased activity of placental 11beta-HSD-2 (type 2 isoform of 11beta-hydroxysteroid dehydrogenase) activity can increase fetal exposure to maternal cortisol, which programmes the fetus for later hypertension and metabolic disease. The placenta appears to function as a nutrient sensor regulating nutrient transport according to the ability of the maternal supply line to deliver nutrients. By directly regulating fetal nutrient supply and fetal growth, the placenta plays a central role in fetal programming. Furthermore, perturbations in the maternal compartment may affect the methylation status of placental genes and increase placental oxidative/nitrative stress, resulting in changes in placental function. Intervention strategies targeting the placenta in order to prevent or alleviate altered fetal growth and/or fetal programming include altering placental growth and nutrient transport by maternally administered IGFs (insulin-like growth factors) and altering maternal levels of methyl donors.