Impaired Placentation Research Articles

Randomized, Controlled Trial Using Low-Dose Aspirin in the Prevention of Preeclampsia in Women With Abnormal Uterine Artery Doppler at 23 Weeks Gestation

In preeclampsia, the endothelial production of prostacyclin, a vasodilator and inhibitor of platelet aggregation, is reduced. At the same time, the production of thromboxane, a vasoconstrictor that promotes platelet aggregation, is increased. Aspirin can inhibit cyclooxygenase, which is important for the production of both of these substances, and a recent metaanalysis of 39 studies suggests that its prophylactic use is associated with a moderate reduction in the incidence of preeclampsia. This study evaluated low-dose aspirin as a preventive measure in women considered to be at high risk because of an abnormal uterine artery Doppler flow study. Color and pulsed Doppler screening studies estimated blood flow in the uterine arteries in 19,950 singleton pregnancies at 22 to 24 weeks gestation. More than 4% of women had a pulsatility index (PI) above 1.6 and were viewed as being at high risk of uteroplacental insufficiency. A total of 560 women at risk were randomly assigned to receive 150 mg aspirin or placebo daily up to 36 weeks gestation. The 2 groups were similar at baseline. No difference was found between the aspirin-treated women and the control group in the cumulative probability of preeclampsia across the range of gestational age. The respective incidence rates were 18% and 19%, and the rates for preeclampsia requiring delivery before 34 weeks gestation were 6% and 8%, respectively-not a significant difference. Aspirin also did not significantly alter the need for preterm delivery, the chance of a birth weight below the 5th percentile, or the risk of perinatal death or placental abruption. This multicenter randomized trial failed to show benefit from low-dose aspirin in pregnancies with impaired placentation. The risk of preeclampsia and the need for preterm delivery were not reduced.

Maternal-Fetal Flow, Negative Events, and Preeclampsia

The risk for an adverse pregnancy outcome is markedly higher in women with history of preeclampsia. This may stem from impaired placentation in early gestation and from high impedance to flow in uteroplacental circulation. The renin-angiotensin system is one of the mediators of the remodeling of spiral arteries throughout pregnancy. The D allele of the Insertion/Deletion (I/D) polymorphism in the ACE gene has been associated with higher ACE activity, accounting for 47% of the total phenotypic variance of serum enzyme levels. To investigate whether the ACE I/D polymorphism affects maternal uteroplacental and fetal umbilical circulation and the pregnancy outcome in women with a history of preeclampsia, 106 women underwent Doppler examination of uterine arteries resistance index and umbilical artery pulsatility index at the 16th, 20th, and 24th weeks of gestation and were genotyped for the I/D polymorphism. This study found a difference in genotype distribution (P=0.0002) and allele frequency (P<0.0001) between women with and those without preeclampsia recurrence and fetal growth restriction as well as an association (P=0.0007) between DD genotype and risk of recurrent preeclampsia or fetal growth restriction. At the 16th, 20th, and 24th weeks, uterine artery resistance indexes were significantly lower in II, higher in DD, and intermediate in ID genotype carriers, whereas the umbilical artery pulsatility index values were significantly higher in the DD group in comparison to ID and II genotypes. The current study shows that the ACE I/D polymorphism affects uteroplacental and umbilical flows and the recurrence of an adverse pregnancy outcome in women with history of preeclampsia.

Second-trimester uterine artery Doppler screening in unselected populations: a review

Objective: Doppler ultrasound provides a non-invasive method for the study of the uteroplacental circulation. In normal pregnancy, impedance to flow in the uterine arteries decreases with gestation,which may be the consequence of trophoblastic invasion of the spiral arteries and their conversion into low-resistance vessels. Pre-eclampsia and fetal growth restriction are associated with failure oftrophoblastic invasion of spiral arteries, and Doppler studies, in these conditions, have shown that impedance to flow in the uterine arteries is increased. A series of screening studies involving assessmentof impedance to flow in the uterine arteries have examined the potential value of Doppler in identifying pregnancies at risk of the complications of impaired placentation. This review examines the findingsof Doppler studies in unselected populations.Methods: Searches of a computerized medical database were performed to identify relevant studies. Only those studies that provided sufficient datato allow calculation of the performance of the test were included in the analysis. Likelihood ratios were calculated for each study and are reported for pre-eclampsia, fetal growth restriction and perinataldeath as well as for more severe forms of pre-eclampsia and fetal growth restriction.Results: The literature search identified 19 relevant studies, four of which were excluded from the furtheranalysis. The main characteristics and results of the 15 remaining studies provided discrepant results, which may be the consequence of differences in Doppler technique for sampling, the definition of abnormalflow velocity waveform, differences in the populations examined, the gestational age at which women were studied and different criteria for the diagnosis of pre-eclampsia and fetal growth restriction. Nevertheless,the studies provided evidence that increased impedance to flow in the uterine arteries is associated with increased risk for subsequent development of pre-eclampsia, fetal growth restriction and perinataldeath. In addition, women with normal impedance to flow in the uterine arteries constituted a group that have a low risk of developing obstetric complications related to uteroplacental insufficiency.Conclusions:The review suggests that increased impedance to flow in the uterine arteries in pregnancies attending for routine antenatal care identifies about 40% of those who subsequently develop pre-eclampsia andabout 20% of those who develop fetal growth restriction. Following a positive test, the likelihood of these complications is increased by about 6 and 3.5 times, respectively.

Uterine artery Doppler at 11-14 weeks of gestation in chromosomally abnormal fetuses.

To determine whether the major chromosomal abnormalities are associated with impaired placentation in the first trimester of pregnancy. This was a prospective study of 692 singleton pregnancies undergoing fetal karyotyping at 11-14 weeks of gestation. Uterine artery Doppler was carried out and the mean pulsatility index was calculated just before chorionic villus sampling. The fetal karyotype was normal in 613 pregnancies and abnormal in 79, including 39 cases of trisomy 21, 11 of trisomy 18, 11 of trisomy 13, eight of Turner syndrome and 10 with other defects. There were no significant differences in the median value of uterine artery mean PI between any of the individual groups. Although in the combined group of trisomy 18, trisomy 13 and Turner syndrome fetuses, the median pulsatility index (1.60) was significantly higher than in the chromosomally normal group (median pulsatility index, 1.51; P = 0.021), in the majority of abnormal fetuses (24 of 30) mean pulsatility index was below the 95th centile of the normal group (mean pulsatility index, 2.34). There was no significant association between uterine artery mean pulsatility index and fetal nuchal translucency thickness or fetal growth deficit. The high intrauterine lethality and fetal growth restriction associated with the major chromosomal abnormalities are unlikely to be the consequence of impaired placentation in the first trimester of pregnancy.

Hypertension in pregnancy.

Hypertension arising during pregnancy remains one of the two most frequently-cited causes of maternal death in the UK. In some cases, pregnancy is unmasking underlying hypertension, which manifests itself in later life. Pregnant women who develop de novo proteinuric hypertension (pre-eclampsia, PE) can share many risk factors with patients with the metabolic syndrome, such as obesity, dyslipidaemia and insulin resistance. However, more than half the women who develop PE remain normotensive thereafter. There is a genetic component(s) to the disease, but it is most improbable that there is a 'PE gene'. Rather, there are factors such as genetically-determined thrombophilias which are predisposers but not prerequisites. Impaired placentation is a feature, with inadequate invasion of the spiral arteries by syncytiotrophoblast and poor remodelling. However, similar features are found in association with non-hypertensive fetal growth restriction. Prospective studies have suggested a hyperdynamic circulation in early pregnancy, with cardiac output only falling in established disease. Baroreflex sensitivity is decreased in normal pregnancy, and still further decreased in established PE. Activation of endothelial cell function antedates the clinical diagnosis, and has features in common with atherosclerosis. Dyslipidaemia is common in PE and, via oxidation of susceptible lipids, may contribute to endothelial activation. Oxidative 'stress' is increased in PE, perhaps through a variant of the hypoxia-reperfusion phenomenon in the developing intervillous spaces. Such early changes might then lead to the clinically-evident syndrome in susceptible women. PE is a protean, multisystem, multifactorial disease, the causes of which are only slightly less enigmatic than a decade ago.

One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks’ gestation

Objective: To estimate the value of screening for preeclampsia and fetal growth restriction by performing color Doppler assessment of uterine arteries at 23 weeks’ gestation in predicting adverse pregnancy outcome. Methods: Women with singleton pregnancies who attended routine ultrasonography at 23 weeks had color Doppler uterine artery imaging. Bilateral uterine artery notches were noted and left and right uterine artery pulsatility indices (PI) were measured. A mean PI of more than 1.45 was considered increased. Screening characteristics for predicting preeclampsia and delivery of small-for-gestational-age infants were calculated. Results: Of 1757 pregnancies, increased PI was present in 89 (5.1%) and bilateral notches were noted in 77 (4.4%). Twenty-three of 65 women (35.3%; 95% confidence interval [CI] 23.9, 48.2) had increased PI and later developed preeclampsia, and 8 of 10 (80%; 95% CI 44.4, 97.5) with preeclampsia required delivery before 34 weeks. The respective values for women with bilateral notches were 21 of 65 (32.3%; 95% CI 21.2, 45.1) and 8 of 10 (80%; 95% CI 44.4, 97.5). The sensitivity of increased PI was 30 of 143 (21%; 95% CI 14.6, 28.6) for delivery of an infant with birth weight below the tenth percentile and 7 of 10 (70% 95% CI 34.8,93.3) for birth weight below the tenth percentile delivered before 34 weeks. The respective values for bilateral notches were 19 of 143 (13.3%; 95% CI 8.2, 20) and 5 of 10 (50%; 95% CI 18.7, 81.3). Conclusion: A one-stage color Doppler screening program at 23 weeks identified most women who subsequently developed serious complications of impaired placentation associated with delivery before 34 weeks. The screening results were similar when the high-risk group was defined as women with increased PI or bilateral notches.

The role of insulin-like growth factor binding protein-1 phosphoisoforms in pregnancies with impaired placental function identified by doppler ultrasound.

This study was performed to investigate the hypothesis that insulin-like growth factor binding protein-1 (IGFBP-1) is involved in the pathogenesis of trophoblast invasion and impaired placentation in human pregnancy. The role of total and non-phosphorylated IGFBP-1 in women with fetal growth restriction and in high risk pregnancies identified by uterine artery Doppler ultrasound screening was examined. This was a prospective study of women booked for antenatal care having second trimester anomaly scans and Doppler screening between 22-26 weeks gestation. Women were divided into three groups and compared: normal uterine artery Doppler and normal fetal growth (control group, n = 10); abnormal Doppler and normal fetal growth [bilateral uterine artery notches (BN; n = 16); abnormal Doppler and intrauterine growth restriction (IUGR; n = 8)]. Maternal serum was collected, stored and assayed simultaneously for total and non-phosphorylated IGFBP-1. There was elevated total and non-phosphorylated IGFBP-1 (mean 44.99 +/- 12.19 and 29.61 +/- 10.38 microg/l respectively) in the IUGR group compared with controls (mean 17.96 +/- 3.24 and 12.18 +/- 1.55 microg/l, P < 0.05). This finding suggests that the various IGFBP-1 isoforms, the degree of phosphorylation and the ratios of these different forms locally may be important during trophoblast invasion and may be implicated in clinical manifestations of impaired placentation later in the second trimester.

Pregnancy-induced hypertension, antihypertensive drugs and the development of fetal behavioural states

In 21 pregnancies complicated by pregnancy-induced hypertension (PIH) which was treated by antihypertensive drugs (labetalol, nifedipine), fetal behavioural recordings (quiet state, C1F; active state, C2F; no coincidence, NOC) and Doppler measurements of blood flow velocity in the umbilical artery (UA) (resistance index, RI) were made on two occasions (27–32 and 33–36 weeks of gestation). Data were compared to those of a control group of normally grown fetuses ( n = 96); in 15 cases we were able to match fetuses from the study group for age (±1 week) and weight (±150 g) at birth with fetales from a control group. It was the aim of this study to investigate if there are disturbances in the development of fetal behavioural states and if possible disturbances are due to poor fetal growth or to antihypertensive therapy. Our results show that in PIH treated by antihypertensive drugs, there are disturbances in the development of fetal behavioural states with higher percentages of NOC and C1F, lower percentages of C2F, and higher UA RI values. These disturbances are mainly due to coexisting placental impairment and poor fetal growth rather than to nifedipine or labetalol therapy, although these drugs may cause some redistribution of states.

Regulation of corticotropin-releasing hormone release from human placental syncytiotrophoblasts by sodium nitroprusside

Failure of adequate trophoblastic conversion of maternal spiral arteries is associated with intrauterine growth restriction (IUGR). In addition to poor oxygen delivery, raised spiral artery resistance reduces placental intervillous pressure. An iterative type computer model was formed by linking an existing model of the fetus and a new nine cotyledon placental model. Simulation of compression cuffing of the spiral arteries to progressively restrict uteroplacental flow was performed, while observing various fetal and placental variables. Water moved to the fetus in the cotyledonary core villi, and to the mother in the outer villous layers. While the fetus could match villous capillary pressure to changes in intervillous pressure, net transplacental water movement was minimal, but when spiral artery resistance was increased sufficiently to cause mean intervillous pressure to fall below that which the fetus could match, a net flow to the mother appeared. That continued until the resulting fetal blood hemoconcentration produced a sufficient increase in colloid osmotic pressure to restrict further loss. All cells within the fetal-placental unit are then required to operate in an abnormal ionic environment, which may significantly affect systems such as the renin–angiotensin set-point, with implications for post-natal homeostasis such as control of adult blood pressure. Furthermore, in vivo, cells of the feto-placental unit respond to the increased intravascular osmotic pressure by production of intracellular osmolytes in order to match intracellular and vascular/interstitial osmotic pressures. This may explain the observed effects on postnatal water balance in growth restricted infants and could also provide a possible mechanism for the association of the systemic maternal complications associated with impaired placentation and reduced intervillus flow.

Lower density of d2 dopamine receptors in the limbic system of alcohol — preferring rats

Prenatal alcohol exposure leads to impaired fetal growth, brain development, and stillbirth. Placental impairment likely contributes to these adverse outcomes, but the mechanisms and specific vasoactive effects of alcohol that links altered placental function to impaired fetal development remain areas of active research.Recently, we developed magnetic resonance imaging techniques in nonhuman primates to characterize placental blood oxygenation through measurements of T2* and perfusion using dynamic contrast-enhanced magnetic resonance imaging. The objective of this study was to evaluate the effects of first-trimester alcohol exposure on macaque placental function and to characterize fetal brain development in vivo.Timed-pregnant Rhesus macaques (n=12) were divided into 2 groups: control (n=6) and ethanol exposed (n=6). Animals were trained to self-administer orally either 1.5 g/kg/d of a 4% ethanol solution (equivalent to 6 drinks/d) or an isocaloric control fluid from preconception until gestational day 60 (term is G168). All animals underwent Doppler ultrasound scanning followed by magnetic resonance imaging that consisted of T2* and dynamic contrast-enhanced measurements. Doppler ultrasound scanning was used to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. After noninvasive imaging, animals underwent cesarean delivery for placenta collection and fetal necropsy at gestational day 110 (n=6) or 135 (n=6).Fetal weight and biparietal diameter were significantly smaller in ethanol-exposed animals compared with control animals at gestational day 110. By Doppler ultrasound scanning, placental volume blood flow was significantly lower (P=.04) at gestational day 110 in ethanol-exposed vs control animals. A significant reduction in placental blood flow was evident by dynamic contrast-enhanced magnetic resonance imaging. As we demonstrated recently, T2* values vary throughout the placenta and reveal gradients in blood deoxyhemoglobin concentration that range from highly oxygenated blood (long T2*) proximal to spiral arteries to highly deoxygenated blood (short T2*). Distributions of T2*throughout the placenta show significant global reduction in T2* (and hence high blood deoxyhemoglobin concentration) in ethanol-exposed vs control animals at gestational day 110 (P=.02). Fetal brain measurements indicated impaired growth and development at gestational day 110, but less so at gestational day 135 in ethanol-exposed vs control animals.Chronic first-trimester ethanol exposure significantly reduces placental perfusion and oxygen supply to the fetal vasculature later in pregnancy. These perturbations of placental function are associated with fetal growth impairments. However, differences between ethanol-exposed and control animals in placental function and fetal developmental outcomes were smaller at gestational day 135 than at gestational day 110. These findings are consistent with placental adaptation to early perturbations that allow for compensated placental function and maintenance of fetal growth.

Proliferation of villous trophoblast of the human placenta in normal and abnormal pregnancies

The proliferation of villous trophoblast in the human placenta was estimated throughout normal gestation and in term placentae from preeclamptic and smoking mothers by two different methods. These were: 1) labeling of DNA producing cells by bromodeoxyuridine (BrdU) followed by immunohistochemistry using a monoclonal anti-BrdU antibody, and 2) immunohistochemical identification of all proliferating cells by the monoclonal antibody Ki67. Both methods revealed comparable results. In uncomplicated pregnancies there was a remarkable decrease in the labeling indices from early gestation to term. This was the result of a diminution of the number of Langhans' cells, although the cell division rate within the Langhans' cell layer remained nearly constant throughout gestation. A prolongation of the cell cycle in the cytotrophoblast cells at term was indicated by an increase in the Ki67/BrdU ratio. Compared with normal term placentae, there was an increase in the trophoblast proliferation rate in preeclampsia, but not in placentae from smoking mothers. Moreover, the number of Langhans' cells was diminished in placentae from smokers. The results indicate that there are different pathogenetic mechanisms of placental impairment in preeclampsia and in maternal smoking. In preeclampsia an injury to the syncytiotrophoblast seems to lead to a repair hyperplasia of the cytotrophoblast, whereas in maternal smoking, there seems to be a direct toxic effect on the cytotrophoblastic cells.

Interdependence of fetal anomalies and placental impairment following maternal hypervitaminosis D and hypercortisonism.

The variable effect of a given teratogenic substance is not yet completely understood. Some teratogenic effects are known to be influenced by parameters, such as dosage, method of administration, the sensitive embryonic developmental stage, the species and the strain of the animal. Possibly other factors play an additional role.