Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants

Summary. An examination of the maternal vascular response to placentation shows that physiological changes in the placental bed normally extend from the decidua into the inner myometrium. In pre-eclampsia and in a proportion of pregnancies with small-for-gestational age infants (SGA) the physiological changes are restricted to the decidual segments alone. In addition, complete absence of physiological changes throughout the entire length of some spiral arteries is seen in pre-eclampsia and SGA. This new observation is confirmed in a study of basal plates of placentas from abnormal pregnancies. Intraluminal endovascular trophoblast may be seen in the placental bed spiral arteries in the third trimester in pre-eclampsia and SGA, a feature not seen beyond the second trimester in normal pregnancy. These findings point to a defect in the normal interaction between migratory trophoblast and maternal uterine tissues in pre-eclampsia and in SGA.     

Platelet life span in pregnancies resulting in small-for-gestational age infants.

Platelet number and life span were determined in the last trimester of pregnancy in 22 women who were delivered of small-for-gestational age (SGA) infants and in 21 women with infants having normal birth weights. Platelet life span was determined by means of a nonradioisotopic method involving the use of acetylsalicylic acid. Mean platelet life span was 7.2 days in women with SGA infants, which is significantly shorter than the 9.2 days found in the control group. The mean platelet count in the SGA group was 235 x 10(9)/L, whereas in the control group it was 208 x 10(9)/L. These data indicate the existence of a compensated thrombocytolytic state in pregnancies with insufficient fetal growth. This could be explained by an increased platelet consumption in the uteroplacental arterial bed.     

Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses

This study was conducted to investigate the association between uterine artery Doppler flow patterns and uteroplacental vascular pathology in normal and complicated pregnancies in view of the recently described concept of heterogeneous causes of hypertensive pregnancy complications. Forty-three women whose pregnancies were complicated by pre-eclampsia, the HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome and/or small for gestational age (SGA) fetuses and 27 women with normal pregnancies undergoing elective caesarean section were included. We obtained uterine artery Doppler waveforms at a mean of 4 days before delivery. Placental bed biopsies were obtained at caesarean section and analysed for physiological changes and pathological changes. We found that abnormal uterine artery Doppler flow was strongly associated with pregnancy complications. Absence of physiological changes was seen in 58 per cent of complicated pregnancies and 40 per cent of normal pregnancies. Pathological changes were seen in 58 per cent of complicated pregnancies and 53 per cent of normal pregnancies; they occurred in spiral arteries with and without physiological changes, and there was no significant correlation to Doppler results. In conclusion, absence of physiological changes is associated with abnormal uterine artery Doppler flow and pregnancy complications. However, there is a gradient in the severity of uteroplacental vascular pathology and the correlation with pregnancy complications is not as strong as previously thought. There is also a significant degree of uteroplacental vascular pathology in normal pregnancies with normal uterine artery Doppler flow. This variation may be partly due to sampling error, as a typical biopsy contains only one or two spiral arteries. We hypothesize that additional factors might be necessary to induce the clinical syndrome of pre-eclampsia.     

Increased visfatin and leptin in pregnancies complicated by pre-eclampsia

Objective.?To evaluate the role of the adipokines, visfatin and leptin in the pathophysiology of pre-eclampsia and how their concentrations correlate with the severity of the disease and abnormal Doppler velocimetry.

Methods.?A cross-sectional study was carried out in 72 pregnant women (30 patients with mild pre-eclampsia, 20 patients with severe pre-eclampsia and 22 healthy normotensive pregnant women) during the third trimester of pregnancy. The maternal levels of plasma visfatin and serum leptin were determined in all cases by enzyme immunoassay and enzyme-linked immunosorbent assay, respectively. The uterine artery and umbilical artery RI were determined by Doppler analysis in all cases.

Results.?Plasma visfatin levels and serum leptin levels were higher in patients with pre-eclampsia than in the normotensive pregnant women. Six patients with mild pre-eclampsia and five patients with severe pre-eclampsia had abnormal Doppler velocimetry. Visfatin and leptin levels of pre-eclamptic patients with abnormal Doppler velocimetry were significantly higher than they were in those with normal Doppler velocimetry. Serum leptin levels were positively correlated with plasma visfatin level in cases of pre-eclampsia.

Conclusions.?These findings suggest that increased maternal levels of leptin and visfatin may be involved in the pathogenesis of pre-eclampsia, and measurement of these adipokines may be useful in assessment of the severity of disease.     

Spontaneous lymphocyte transformation in pregnancies complicated by pre-eclampsia.

There was no significant difference between the mean spontaneous transformation rates of maternal lymphocytes from normal pregnant women and patients with pre-eclampsia.     

VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia

Objective To measure the mRNA levels of vascular endothelial growth factor and its receptor in the placenta following delivery after uncomplicated pregnancy and after pregnancies complicated by pre-eclampsia.
Setting Rosie Maternity Hospital, Cambridge.
Material Placental biopsies were obtained following delivery by caesarean section in 23 cases of pregnancy presenting at a range of gestational ages with pre-eclampsia. These were compared with biopsies from 20 appropriately matched women with uncomplicated pregnancies.
Main outcome measure mRNA levels of vascular endothelial growth factor (VEGF) and its receptor the fins-like tyrosine kinase (flt), were quantified in total RNA isolated from placental biopsies using the RNAse protection assay. The amount of RNA was compared with that of the housekeeping gene glyceraldehyde 3–phosphate dehydrogenase (GAPDH), used as a standard. Results were expressed as arbitrary optical density units of VEGF/GAPDH and flt/GAPDH.
Results In both control and pre-eclamptic women regression analysis showed that the level of mRNA encoding VEGF declined significantly with gestational age (   P < 0.0001  ). However, levels of VEGF mRNA were significantly lower in the pre-eclamptic women compared with the control women (   P < 0.023  ).
Conclusions This study provides evidence of an abnormality of growth factor expression in the placenta during pregnancies complicated by pre-eclampsia. Such placentae exhibit deficient growth and differentiation of terminal villi and reduced fetal capillary branching and reduced levels of VEGF could well account for these morphometric changes. This finding provides a molecular explanation for this abnormal placental development and points to VEGF as a factor in the aetiology of pre-eclampsia and its complications.     

Computerized cardiotocography in pregnancies complicated by maternal asthma

Objective: The aim of the present study was to investigate the FHR parameters in term pregnancies complicated by asthma. Study design: prospective cross-sectional study performed between July 2008 and November 2009. Twenty-one singleton pregnancy between 36 and 40 weeks gestation with diagnosis of maternal asthma and no current use of oral corticosteroids were compared with 30 pregnancies without morbidities at the same gestational age. The computerized cardiotocography (System 8002, Sonicaid) was performed and 30?min analysis was studied. Statistical analysis included Student’s t-test or Mann–Whitney U test for comparisons between groups. Categorical data were compared using the χ²-test or Fisher’s exact test. Results: There were no significant differences in FHR parameters analyzed by computerized cardiotocography: basal FHR (p?=?0.80), number of accelerations >10 bpm (p?=?0.08) or > 15 bpm (p?=?0.20), duration of high episodes (p?=?0.70), duration of low episodes (p?=?0.46) and STV (p?=?0.66). Asthmatic mothers presented mean number of fetal movement per hour significantly lower than control group (34.6?±?28.2 vs. 60.6?±?43.1, p?=?0.02). Conclusion: Computerized cardiotocography demonstrates no association between the abnormal parameters of FHR and maternal asthma in term pregnancies. Maternal asthma was associated with less fetal movements per hour, suggesting further studies on the counting of fetal movements in pregnant women with asthma.     

Head circumference and long-term outcome in small-for-gestational age infants

OBJECTIVES: To assess risk factors for the growth and development of small-for-gestational age (SGA) infants whose birth weight was less than the 10(th) percentile. PATIENTS AND METHODS: SGA infants who were admitted to the neonatal intensive care unit from 1995 to 1998 were enrolled in the study. Fifty-six SGA infants, having no chromosomal abnormalities, inherited diseases, TORCH infections, major anomaly and/or multiple birth, were divided into 34 asymmetrical and 22 symmetrical SGA infants by >or= or <10(th) percentile head circumference (HC) at birth. The physical growth including HC, and the developmental quotient (DQ) and intelligent quotient (IQ) scores were evaluated up to 6 years of age. RESULTS: Symmetrical SGA infants had lower levels of weight, height and HC, but not of total DQ at 3 years or IQ scores at 6 years of age than asymmetrical SGA infants. The 21 SGA infants who had a HC less than the 10(th) percentile at 1 year of age (non-catch-up group) showed lower total DQ (mean 96 vs. 105) and IQ (82 vs. 102) scores than 34 SGA infants who had not (catch-up group). CONCLUSIONS: These results suggested that psychomotor development of SGA infants depended on the HC at 1 year of age rather than that at birth.     

The human tumor-associated antigen RCAS1 in pregnancies complicated by pre-eclampsia

The human tumor-associated antigen RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is considered to play a role in the escape of tumor cells from immune surveillance and, at the same time, participates in the inhibition of the maternal immune response during pregnancy. The aim of our study was to investigate the expression of tumor-associated RCAS1 protein in the placenta and amniotic membranes and to assess and compare its concentration in amniotic fluid, maternal and cord blood sera in pregnancies complicated by pre-eclampsia. Samples were obtained from women with pre-eclampsia (N=9), pre-eclampsia with IUGR (N=4), normotensive IUGR (N=7) and healthy term controls (N=25) after delivery. Placentas were studied by immunohistochemistry, Western blot analysis and real-time (RT)-PCR. For assessment of RCAS1 protein concentrations in biological fluids, ELISA was performed. RCAS1 mRNA expression in the placentas of pre-eclamptic patients was significantly lower than in controls (p<0.01). The maternal blood serum RCAS1 protein concentration in the pre-eclampsia cases was also significantly lower than in controls (p=0.0207). The other study groups did not differ significantly. This study reveals the possible role of the RCAS1 protein in the development of pre-eclampsia through an immunological pathway.     

Decreased maternal serum leptin in pregnancies complicated by preeclampsia

OBJECTIVE: To determine whether circulating levels of leptin differed between women with preeclampsia and women who had an uncomplicated pregnancy. METHODS: Maternal and umbilical venous plasma leptin concentrations obtained at delivery were compared in 36 pairs of women with either preeclampsia or normal pregnancy, matched 1:1 for prepregnancy body mass index and fetal gestational age at delivery. RESULTS: Prepregnancy body mass index was 21.1 +/- 2.1 kg/m2 in either study group (range 17.6-25.3 kg/m2 and 17.7-25.3 kg/m2 in the normal and preeclamptic group, respectively). Mean fetal gestational age at delivery was 40.1 +/- 1.3 weeks and 40.1 +/- 1.2 weeks in the normal and preeclamptic group, respectively. Median leptin concentrations were significantly lower (P <.0001) in women with preeclampsia (8.3 ng/mL, range 3.5-20.0 ng/mL) than in normal pregnant women (20.2 ng/mL, range 6.0-63.7 ng/mL). Median umbilical venous leptin was not significantly different between groups (preeclampsia 11.8 ng/mL, range 2.0-37.2 ng/mL; normal 7.6 ng/mL, range 1.6-24.3 ng/mL; P = .377). Umbilical venous leptin levels correlated positively with birth weight in both groups (preeclampsia rho = 0.501, P = .002; normal rho = 0.517, P = .001), whereas no correlations were found between maternal and fetal hormone concentrations. Maternal leptin concentrations did not correlate with birth weight. CONCLUSION: Our data suggest that the correlation between umbilical venous leptin concentration and birth weight is independent of the presence of preeclampsia. Given the inconsistency in literature concerning circulating leptin levels in preeclampsia, further studies should investigate the regulatory systems of leptin in preeclampsia.     

Umbilical cord serum vascular endothelial growth factor (VEGF) levels in normal pregnancies and in pregnancies complicated by preterm delivery or pre-eclampsia.

OBJECTIVES: The aim of this study was to determine whether increased levels of vascular endothelial growth factor (VEGF) are implicated in the pathogenesis of pre-eclampsia and in preterm delivery. METHODS: Umbilical cord serum VEGF levels from women with uncomplicated term pregnancies (control group, n=24), with pregnancies complicated by pre-eclampsia (n=21), or with preterm delivery (n=29) were compared. Statistical analysis was performed using the Mann-Whitney U-test, the t-test, and Smirnoff-Kolmogorov test. RESULTS: The mean VEGF concentration was significantly higher in the women with pre-eclampsia than in women from the control group (P<0.01). There were also increased but not significantly higher VEGF concentrations in the preterm delivery group compared with the control group (P=0.16). CONCLUSIONS: Our study results support previous findings that raised umbilical cord serum VEGF levels might be correlated with the clinical development of pre-eclampsia and, in some circumstances, of preterm delivery.     

Metastin levels in pregnancies complicated by pre-eclampsia and their relation with disease severity

Aims: To evaluate the role of metastin levels in the pathophysiology of pre-eclampsia and to determine whether there is a relationship between the severity of the disease and Doppler velocimetry measurements. Methods: This cross-sectional study included 89 pregnant women (50 healthy normotensive pregnant women, 15 patients with mild pre-eclampsia, and 24 patients with severe pre-eclampsia) at the third trimester of pregnancy. The maternal levels of plasma metastin were determined by enzyme-linked immunosorbent assay. The umbilical artery and uterine artery blood flow velocities were measured by transabdominal color and pulsed Doppler ultrasound. Results: Plasma metastin levels were lower in patients with pre-eclampsia than those in the normotensive pregnant women. Four patients with mild pre-eclampsia and seven patients with severe pre-eclampsia had abnormal Doppler velocimetry findings. Metastin levels of pre-eclamptic patients with abnormal Doppler velocimetry findings were significantly lower than those in patients with normal Doppler velocimetry findings. Plasma metastin levels negatively correlated with proteinuria in 24 hours and with mean arterial pressure in the cases of pre-eclampsia. Conclusions: The findings suggest that decreased maternal concentrations of plasma metastin may be involved in the pathogenesis of pre-eclampsia. Plasma metastin levels may be useful in the assessment of the severity of pre-eclampsia. However, further trials are needed to clarify the role of metastin in pre-eclampsia.     

Umbilical cord plasma homocysteine concentrations at delivery in pregnancies complicated by pre-eclampsia

Aim: To determine whether homocysteine concentrations in umbilical cord plasma of neonates born to mothers with pre-eclampsia are elevated compared to concentrations in neonates born to normotensive women.
Method: Maternal blood from eight women with pre-eclampsia and ten women without pre-eclampsia was collected on admission for labour. Cord blood was collected from these same pregnancies at delivery. Plasma was extracted and stored at −70°C. Samples were batch-analysed for homocysteine.
Result: Maternal plasma homocysteine levels were observed to be significantly higher in the pregnancies complicated by pre-eclampsia compared to the control pregnancies ( P  = 0.043) with median levels of 5.4 µmol/L (interquartile range (IQR) 4.6–7.9; range 3.6–16.7) versus 4.1 µmol/L (IQR 3.4–5.1, range 3.1–6.7). Homocysteine concentrations in umbilical cord plasma in pregnancies complicated by pre-eclampsia were also significantly higher compared to those in normotensive pregnancies ( P  = 0.016) with median concentration levels of 5.3 µmol/L (IQR 4.8–7.2, range 2.5–16.6) versus 3.8 µmol/L (IQR 2.8–4.4, range 0.8–1.6).
Conclusion: Both maternal and umbilical cord plasma homocysteine concentrations were elevated in pregnancies complicated by pre-eclampsia compared to normotensive controls.     

Child development after pregnancies complicated by low urinary estriol excretion and pre-eclampsia

A study is reported of maternal estriol excretion and subsequent child development in 16 pregnancies complicated by pre-eclampsia. Eight mothers with pre-eclampsia had abnormally low estriol excretion patterns and 4 of their children were small for dates. On follow-up examination, 3 of these children had major problems in development or function: microcephaly, seizure disorder, and developmental retardation with hyperactivity. Neurological abnormalities on follow-up examination were confined to children whose mothers had chronically low rather than precipitately dropping estriol levels. Eight mothers had normal estriol excretion with toxemia, and all 8 children weighed more than 2,500 grams and were normal on follow-up. The data suggest that if infants are of appropriate gestational ages when precipitate drops in maternal estriol excretion occur the infants should be delivered immediately because they do well. However, infants delivered after chronically low maternal estriol values are frequently defective.     

Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia

Objective To compare serum levels of angiogenic growth factors vascular endothelial growth factor (VEGF), placental growth factor (PIGF) and angiogenin in pre–eclamptic women and matched controls.
Design Retrospective analysis of −70°C stored serum of women who developed pre-eclampsia and matched controls.
Setting Department of Gynaecology and Obstetrics, St Elisabeth Hospital, Curaqao, Netherlands Antilles.
Sample Thirty women with pre-eclampsia and 30 normotensive controls matched for age and gestation.
Results VEGF and PIGF serum levels were significantly lower in pre–eclamptic pregnancies, compared with controls (VEGF 0.31 ± 1.20 vs 18.30 ± 24.97 pg/mL,   P = 0.0004  ; PIGF 54.19 ± 32.05 vs 497.95 ± 340.51 pg/mL,   P < 0.0001  ). Matched couple analysis showed VEGF serum concentrations to be lower in the majority of pre–eclamptic women and PIGF concentrations to be lower in all pre–eclamptic women. Angiogenin serum levels showed no statistical significant difference between pre–eclamptic pregnancies and controls (523.68 ± 367.55 vs 670.41 ± 251.54 ng/mL,   P = 0.058  ), with matched couple analysis showing no clear pattern.
Conclusions Decreased serum levels of VEGF and PIGF characterise, and therefore seem to be of importance during (the development of), pre-eclampsia. This selective deficit of angiogenic growth factors might in part explain the shallow placentation found in this pregnancy complication.