Severe Fetal Growth Retardation Research Articles

Аналіз перинатальних наслідків у жінок із високим і критичним рівнем співвідношення sFlt-1/PlGF

Purpose - to analyze the maternal and perinatal outcomes of pregnancy in women with high and critical water-soluble tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratios. Materials and methods. A prospective analysis of the course of pregnancy in 137 women with a threat of miscarriage aged 20 to 47 years was performed (the Group I - 60 patients with retrochorionic hematoma (RCH), the Group II - 77 patients with a threat of pregnancy termination without hematoma). Additionally, the level of sFlt-1/PlGF ratio was determined at gestational ages 19-23+6 weeks and 32-33+6 weeks using TRACE-technology (BRAHSMS Kryptor). Patients with a ratio value of more than 110 were included in the further study group. The antenatal risk of perinatal complications was assessed retrospectively in all patients according to the adapted Alberta perinatal health program scale. Results. The mean age of women in the Group I was 31.2±0.6 (95% CI: 30.0-32.4) years, and in the Group II - 32.2±0.6 (95% CI: 31.0-33.3) years (p=0.243 by t-test). The calculation of the risk of pre-eclampsia (PE) in women of the thematic groups using the Fetal medicine foundation (FMF) calculator «Preeclampsia risk assessment first and second trimester» revealed a high risk of its development in 28 (46.7%) women of the Group I against 23 (29.9%) women of the Group II (p=0.044 at 2). An analysis of the results of the sFlt-1/PlGF ratio at 19-23+6 weeks revealed a high or critical value in 7 (5.1%) cases. During the study of sFlt-1/PlGF at 32-33+6 weeks in both groups, cases of high or critical values of the ratio were observed in women who had no changes in the sFlt-1/PlGF ratio during the previous study at 19-23+6 weeks: in 3 cases - high value of the sFlt-1/PlGF ratio, in 1 case - critical. In all cases of high and critical levels of the ratio, the pregnancy ended prematurely due to the development of moderate or severe PE and fetal growth retardation. Conclusions. A high sFlt-1/PlGF ratio during the second half of pregnancy is associated with placental dysfunction (PD) and has a high predictive value. An important role is played by the gestational age at which these changes were first detected, as well as by a burdened medical history. The occurrence of RCH in early placentation increases the risk of developing PD and the obstetric complications associated with it. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

ВЛИЯНИЕ АКТИВНОГО И ПАССИВНОГО КУРЕНИЯ НА РИСК РАЗВИТИЯ ПРЕЖДЕВРЕМЕННЫХ РОДОВ И ДРУГИХ БОЛЬШИХ АКУШЕРСКИХ СИНДРОМОВ

Preterm birth is one of the leading causes of infant and neonatal mortality. Progressive placental and hypertensive disorders and pre-eclampsia often increase the proportion of induced preterm births. The study aims. There is conflicting evidence in the literature about the association of active and passive smoking with the risk of these gestational complications. The present study analysed the complications of pregnancy in smoking and non-smoking women according to the timing of delivery. According to the results, smoking is a significant risk factor for preterm birth, placental and hypertensive disorders. The chances of severe pre-eclampsia and fetal growth retardation were higher in women who smoked. The likelihood of these complications increases with the duration of smoking.

Pregnancy complications in G20210A mutation carriers associated with high prothrombin activity

ObjectiveTo study the association between high activity of Factor II (prothrombin) in blood plasma with G20210A mutation and the development of great obstetrical syndromes.Material and methodsA prospective clinical cohort study was conducted on 290 pregnant women (average age 31.7 ± 4.7 years old). The main group was made up of 140 G20210A patients, while the control group comprised 150 women with the wild G20210G type. The aim was to evaluate the activity of Factor II in the venous blood plasma during the stages of pregnancy with regard to trophoblast invasion waves. As per results, association analysis of Factor II activity value and gestational complications was carried out.ResultsIn the control group, the median (Me) of Factor II activity ranged from 108% (preconception period) to 144% (pregnancy) [95% CI 130–150]. In patients with the GA type, the value was significantly higher in related periods, ranging from 149 to 181% [95% CI 142–195], p < 0.0001. With Factor II activity ranging from 148.5 to 180.6%, pregnancies in the main group had no complications. Higher levels of Factor II activity were associated with the development of early and/or severe preeclampsia (PE) and fetal growth retardation (FGR).ConclusionThe data obtained regarding Factor II activity in blood plasma, juxtaposed with the development of great obstetrical syndromes, allow to assume that manifestation of G20210A in early and/or severe PE and FGR is associated with this coagulation factor’s level of activity. Threshold value of the Factor II activity with G20210A mutation, allowing to predict the development of PE, comprised 171.0% at the preconception stage (AUC – 0.86; p < 0.0001) and within 7–8 weeks of gestation it was 181.3% (AUC – 0.84; p < 0.0001).

Gestational complications of the prothrombin G20210A mutation related to prothrombin activity

Aim: to study the association between prothrombin activity in the blood plasma and gestational complications in women with the prothrombin G20210A mutation.Materials and methods. A prospective clinical cohort study including 290 pregnant women aged 18 to 45 years was conducted from 2012 to 2018. Two cohorts were formed: a study group of 140 patients with the GA genotype and a control group of 150 women with the GG genotype. In the groups, the activity of prothrombin (Factor II) in the venous blood plasma was evaluated during pregnancy. The stages of cytotrophoblast invasion were taken into account when relating the prothrombin activity to gestational complications.Results. The median prothrombin activity in the control group ranged from 108 % during the preconception period to 144 % during pregnancy (95 % CI = 130–150). In the study group with the GA genotype, the activity was significantly higher at the same periods: from 149 to 181 % (95 % CI = 142–195; p &lt; 0.0001). With the prothrombin activity from 148.5 to 180.6 %, the pregnancy in the study group progressed normally. Higher levels of prothrombin activity were associated with early and/or severe preeclampsia (PE), and fetal growth retardation (FGR).Conclusion. The obtained data on prothrombin activity in the blood plasma during pregnancy complications suggest that the manifestation of the GA genotype in the form of early and/or severe PE and FGR is associated with the level of plasma prothrombin activity. The threshold value of Factor II activity was calculated for patients with the G20210A mutation; based on this value it becomes possible to predict PE at the preconception stage (171.0 %; AUC – 0.86; p &lt; 0.0001) and at a gestational age of 7–8 weeks (181.3 %; AUC – 0.84; p &lt; 0.0001).

Fertility outcomes following pelvic embolization in women with acquired uterine arteriovenous malformation

ObjectiveAcquired uterine arteriovenous malformation (UAVM) is a rare, life-threatening disease. Angiography with uterine arterial embolization (UAE) is the diagnostic tool and a choice of fertility-sparing treatment. Here, we present a series of five successful pregnancies after embolization of UAVM. Case reportsThree reproductive aged women were treated for UAVM, resulting in five successful pregnancies. Their past history suggested that three cases had had previous uterine procedures, including second trimester abortion and elective dilatation and curettage. Intermittent heavy vaginal bleeding was the primary symptom of UAVM. One patient with anemia had two ineffective embolizations and achieved a singleton pregnancy after the third embolization. However, intrauterine fetal demise with severe fetal growth retardation was noted on the 28th gestation week. The other two women had temporary ovulation disorder after UAE. After Clomiphene Citrate (CC) treatment, successful pregnancies were achieved and carried to term uneventfully. ConclusionUAE is an acceptable method for preserving fertility and treatment in women with symptomatic UAVMs.

Imprinted disorders and growth

Fetal growth is a complex process. Its restriction is associated with morbidity and long-term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are two imprinting disorders with opposite fetal growth disturbance. SRS is leading to severe fetal and postnatal growth retardation with severe feeding difficulties during early childhood and long-term metabolic consequences and BWS is an overgrowth syndrome with an enhanced risk of tumors during childhood. Epigenetic (abnormal methylation at the imprinting center regions) or genetic (mutations, duplications, uniparental disomy [UPD]) including defects of imprinted genes on chromosome 11 (BWS and SRS), 7 (SRS) and more recently 14 (SRS) have been identified in these two syndromes. In humans, the 11p15 region contains genes important for the regulation of fetal and postnatal growth. This region includes two imprinted domains: the IGF2/H19 domain regulated by imprinting center region 1 (ICR1 or H19/IGF2:IG-DMR) and the CDKN1C/KCNQ1OT1 domain regulated by ICR2 (or KCNQ1OT1: TSS DMR).

Содержание аргинина и аргиназы в плазме крови у беременных с задержкой роста плода

The objective: to determine arginine and arginase levels in the blood serum of pregnant women with intrauterine growth retardation of different severity. Patients and methods. The study included 100 pregnant women (from 23 to 40 weeks of gestation). The main group consisted of 80 pregnant women with intrauterine growth retardation. The control group consisted of 20 women with physiological course of pregnancy. The patients of the main group were divided into three clinical groups regarding intrauterine growth retardation staging. Group I included 38 pregnant women with stage I IUGR, 22 pregnant women with stage II IUGR were in group II and 20 pregnant women with stage III IUGR – in group III. L-arginine concentration was determined in the blood serum by the method of T.L. Aleinikova et al [1], arginase activity – by the method of J.W. Geyer, D. Dabich [4]. The statistical analysis was performed by using standard computer programs: STATISTICA 6.0, Microsoft Excel, ANOVA. Statistically significant difference was considered at p&lt;0.05. Results. In the study the reduced level of free arginine in the main group of pregnant women with intrauterine growth retardation of different severity was determined if compared with the control group. Fetomaternal gradient of arginine is reduced significantly due to increasing activity of the enzyme arginase, which competitively uses amino acid. Conclusions. The level of reduced free arginine in the blood serum of pregnant women with intrauterine growth retardation is directly proportional to the severity of fetal growth retardation: the more severe fetal growth retardation, the more marked arginine deficiency. For correcting metabolic disorders in pregnant women with intrauterine growth retardation it is recommended to administer L-arginine containing drugs. Key words: L-arginin, arginase, blood serum, pregnant women with intrauterine growth retardation.

Severe ascites as the primary symptom of fulminant postpartum HELLP syndrome: a case report

Previous studies show that HELLP syndrome occurring in postpartum period was more dangerous to both fetus and the mother than if presented before delivery. So far, there is a lack of screening or predictive tests for postpartum HELLP syndrome in clinical practice. Case: Here the authors report a rare case of postpartum HELLP syndrome with severe ascites as the primary symptom. The patient was diagnosed with severe preeclampsia and fetal growth retardation at 34+2 weeks gestation and received anti-hypertensive therapy. Severe ascites were found intraoperatively during emergency caesarean section. On the second postoperative day, complete HELLP syndrome was diagnosed. This case gradually complicated by hypoproteinemia, acute renal failure, severe anaemia, and infection and required renal haemodialysis, blood transfusion, and other supportive treatments for about one month. Conclusion: Although this case has a fulminant and long course, it has a well clinical prognosis and also shows that severe ascites may be a clue for postpartum HELLP syndrome in patient with severe preeclampsia.

The clinical characteristics and early detection of postpartum choriocarcinoma.

This study aimed to identify the clinical and demographic characteristics and prognosis of patients with conditions diagnosed with postpartum choriocarcinoma based on the International Federation of Gynecology and Obstetrics 2000 prognosis scoring system or based on pathologically confirmed choriocarcinoma and to analyze the patients' clinical symptoms for early detection of this disease. Between January 1983 and August 2013, 24 consecutive women with postpartum choriocarcinoma were treated at 2 hospitals. Data on clinical and demographic characteristics, including initial presenting symptoms, type of antecedent pregnancy, fetal complications, and prognosis of these patients, were analyzed. According to the time interval between the previous delivery and the onset of disease, patients were divided into 2 groups: the short and long interval groups. The most common symptom among the 24 patients with postpartum choriocarcinoma was irregular vaginal bleeding (14/24); in some cases, bleeding was caused by metastatic foci (7/24). Massive genital bleeding causing emergency hysterectomy and several obstetric complications, such as unknown severe fetal anemia and fetal growth retardation, was only observed in the short interval group. The overall primary remission rate was 91.7%. The most common symptom of patients with postpartum choriocarcinoma in the short and long interval groups was genital bleeding, and the overall prognosis may be improved by introduction of an appropriate chemotherapy regimen. Careful pathological examination of the placenta is needed in cases of fetomaternal hemorrhage, unknown fetal anemia, and abnormal obstetric events, including premature delivery, still birth, and infantile growth retardation, for the early detection of intraplacental choriocarcinoma.

Highly significant association between two common single nucleotide polymorphisms in CORIN gene and preeclampsia in Caucasian women.

Preeclampsia is a frequent medical complication during pregnancy. Corin, a serine protease which activates pro-atrial natriuretic peptide, has recently been shown to be involved in the pathophysiology of preeclampsia. The aim of this study was to search for CORIN gene variations and their association to preeclampsia in Caucasian and African women. Our study population was composed of 571 pregnant women (295 with preeclampsia and 276 normotensive controls) matched for maternal and gestational age, and ethnic origin. The 22 exons of the CORIN gene were sequenced in a discovery sample (n = 260), where 31 single nucleotide polymorphisms were identified. In a replication sample (n = 311), 4 single nucleotide polymorphisms were tested. Two minor alleles (C for rs2271036 and G for rs2271037) were significantly associated to preeclampsia. Adjusted odds ratios [95% confidence interval] were 2.5 [1.2–3.8] (p = 0.007) and 2.3 [1.5–3.5] (p = 1.3×10−4), respectively. These associations were ethnic-specific, as only found in the Caucasian of subjects (odds ratio = 3.5 [1.8–6.6], p = 1.1×10−4; odds ratio = 3.1 [1.7–5.8], p = 2.1×10−4, for each single nucleotide polymorphism, respectively). The two single nucleotide polymorphisms are in almost perfect linkage disequilibrium (r2 = 0.93). No specific association was found with severe preeclampsia, early-onset preeclampsia nor fetal growth retardation. In conclusion, this is the first report of a highly significant association between these two single nucleotide polymorphisms in CORIN gene and preeclampsia. Our findings further support the probability of a critical role of corin in preeclamspia pathophysiology at the uteroplacental interface.

PP117. Measurement of sFlt-1 and PlGF for prediction of pregnancy associated diseases

IntroductionSevere preeclampsia is associated with characteristic changes of sFlt-1 and PlGF levels in the maternal serum. ObjectivesThe aim of our study is the determination of the predictive value of sFlt-1 and PlGF for preeclampsia and other pregnancy associated diseases in women with a pathological uterine Doppler measurement during the second trimester of pregnancy. MethodsAn updated analysis of an ongoing prospective trial will be presented. Criterion of inclusion was a bilateral pathological uterine Doppler measurement with an increase of the resistance index (RI) >95th percentile and/or a bilateral postsystolic notch during 19 and 24 weeks. Ratio of sFlt-1 and PlGF was repeatedly measured during pregnancy using a full-automated system (Elecsys®, Roche). ResultsPresently, we recruited 36 patients. Full data are available from 17 patients. Out of these in 23.5% (n=4) a delivery before 37 weeks was indicated. 41% of all newborns (7/17) showed a birth weight <5th percentile. 23.5% of all patients developed a hypertensive pregnancy disorder but without fulfilling the criterions of preeclampsia. Only two patients had a sFlt-1/PlGF ratio >95th percentile. In both cases we found severe fetal growth retardation. One of them developed a pregnancy related hypertension based on an antiphospholipid syndrome. ConclusionThe additional measurement of the sFlt-1/PlGF ratio in a high risk group of pregnancies may improve the prediction of severe pregnancy related diseases during the second trimester. But keeping the low incidence of severe preeclampsia in mind, the measurements seem to be only usefulness in a high risk population. Although we reported presently only of a small part of our study population the sFlt-1/PlGF ratio did not revealed a good specificity for prediction of preeclampsia. Pathological values were also found in cases with fetal growth retardation without signs of preeclampsia.

Role of Epigenetics in the Placenta: Alterations in DNA Promoter Mmethylation and Limprinted Genes

Many researchers are focusing on epigenetic regulation in the placenta. Because the proper development and function of the placenta are crucial for the normal healthy growth and survival of the developing fetus, the study of epigenetic alterations is providing critical insights into the biology of fetal development and the pathogenesis of complications in pregnancy. One epigenetic alteration is genomic imprinting. Alleles from both the father and mother are necessary for normal human and placental development. For example, the paternally expressed IGF2 gene and maternally expressed H19 gene are located in 11p15.5 and they are coordinately regulated by differentially methylated regions (DMRs). The main phenotype of Silver-Russell syndrome is severe fetal growth retardation (FGR) that is caused by a reduction in IGF2 transcription as a result of a loss of methylation at the H19 DMR. Hypermethylation at the H19 DMR is found in 30% of cases of Beckwith-Wiedemann syndrome and the overgrowth phenotype. The other main mechanism is a promoter DNA methylation. Hypomethylation of a promoter of the SERPINA3 gene in the placenta is associated with FGR and preeclampsia. These clues to the epigenetic phenomena involved in the processes of human development and disease in pregnancy have been found in recent years.

L27. Management of non severe gestational hypertension through the modulation of total vascular resistance

sometimes it is necessary. It is indicated to deliver when some specific maternal or fetal conditions develop. Maternal indications for delivery include: platelet count under 100,000, progressive liver function deterioration, progressive renal function deterioration, suspected abruptio placentae, refractory severe hypertension (>160/110), persistent severe headache or visual changes, persistent severe epigastric pain or emesis. Fetal indications for delivery are: severe fetal intrauterine growth retardation, low umbilical artery systolic/diastolic ratio by doppler ultrasound, non-reassuring fetal testing, oligohydramnios. If the gestation is greater than 34 weeks, delivery after stabilization is recommended.

291 Echocardiographic assessment of myocardial function using automatic functional imaging in IUGR fetuses with high risk of cardiac failure: a preliminary study

Severe fetal vascular growth retardation leads most often spontaneously to cardiac failure and fetal death. Fetal cardiac monitoring is therefore a priority in order to decide on ideal timing for fetal extraction. The assessment of cardiac function in fetuses using conventional 2D imaging has always been challenging, due to the lack of adapted algorithm to the specific fetal cardiac geometry. Automatic Functional Imaging (AFI) is a new angle and Doppler independent technique, based on 2D analysis of the myocardial deformation (or Strain). It allows to measure the strain of a chosen myocardial region of interest (ROI): right or left ventricle or both. Assess cardiac function with AFI in fetuses with severe In Utero Growth Restriction (IUGR) and high risk of cardiac failure, and compare to normal fetuses. We recruited prospectively in a single institution 24 normal fetuses (group I), 17 fetuses with severe IUGR (estimated weight <3d percentile) and umbilical Doppler's Pulsatility Index >95th percentile (group II) and 8 fetuses with severe IUGR (estimated weight <3d percentile) without umbilical Doppler's anomaly (group III). Myocardial strain and strain rate of left, right and total ventricles (respectively LV, RV, TV) were measured from a 4 chamber view (figure 1 and 2) and compared between groups. No correlation was found between gestational age and strain and strain rate in normal fetuses. Feasibility was around 82%, and reproducibility was good. LV and TV strain was lower in group II and III compared to group I (respectively 21.9, 20.9 vs 25.1% and 19.9, 18.7 vs 22.9% (p<0,05)). Surprisingly, RV strain was not different between group I and II but was lower in group III (p<0.05). Strain rate was not different between groups. AFI is a new technique allowing cardiac function measurement in fetuses. It is of particular interest in the follow up of pregnancy with high risk of fetal cardiac failure.

Endothelial Expression of Beta‐1 Integrin Is Required for Embryonic Vascular Patterning and Postnatal Vascular Remodeling

The largest subgroup of integrins is that containing the β1 subunit. Global deletion of β1 integrin expression results in embryonic lethality at ~E5, a developmental time point too early to determine the effects of this integrin on vascular development. To elucidate the specific role of β1 integrin in the vasculature, we conditionally deleted the β1 gene in the endothelium using Cre/LoxP techniques. Homozygous deletion of β1 integrins in the endothelium resulted in failure of normal vascular patterning, severe fetal growth retardation, and embryonic death at E9.5‐10, although there were no overt effects on vasculogenesis (Fig. 1). Heterozygous endothelial β1 gene deletion did not diminish fetal or postnatal survival, but reduced β1 subunit expression in endothelial cells from adult mice approximately 40%. These mice demonstrated abnormal vascular remodeling in response to experimentally altered in vivo blood flow, and diminished vascularization in healing wounds (Fig. 2). These data demonstrate that endothelial expression of β1 integrin is required for developmental vascular patterning, and that endothelial β1 gene dosing has significant functional effects on vascular remodeling in the adult. Understanding how β1 integrin expression is modulated may have significant clinical importance.

Endothelial Expression of β1 Integrin Is Required for Embryonic Vascular Patterning and Postnatal Vascular Remodeling

The largest subgroup of integrins is that containing the beta1 subunit. beta1 integrins have been implicated in a wide array of biological processes ranging from adhesion to cell growth, organogenesis, and mechanotransduction. Global deletion of beta1 integrin expression results in embryonic death at ca. embryonic day 5 (E5), a developmental time point too early to determine the effects of this integrin on vascular development. To elucidate the specific role of beta1 integrin in the vasculature, we conditionally deleted the beta1 gene in the endothelium. Homozygous deletion of beta1 integrins in the endothelium resulted in failure of normal vascular patterning, severe fetal growth retardation, and embryonic death at E9.5 to 10, although there were no overt effects on vasculogenesis. Heterozygous endothelial beta1 gene deletion did not diminish fetal or postnatal survival, but it reduced beta1 subunit expression in endothelial cells from adult mice by approximately 40%. These mice demonstrated abnormal vascular remodeling in response to experimentally altered in vivo blood flow and diminished vascularization in healing wounds. These data demonstrate that endothelial expression of beta1 integrin is required for developmental vascular patterning and that endothelial beta1 gene dosing has significant functional effects on vascular remodeling in the adult. Understanding how beta1 integrin expression is modulated may have significant clinical importance.

Place du caryotype placentaire dans l'enquête étiologique des retards de croissance intra-utérins sévères précoces. À propos d'un cas

Except for cases due to maternal hypertension, severe and early intrauterine growth retardations are most usually due to fetal abnormalities. We report a case of confined placental homogenous tetraploidy associated with major fetal growth retardation leading to the premature delivery of a life born baby with a normal caryotype. We discuss the interest of chorionic villus sampling in cases of unexplained severe fetal growth retardation.

Discordant twin growth in utero and differences in blood pressure and endothelial function at 8 years of age

Low birth weight is associated with increased prevalence of hypertension and cardiovascular disease in adults. The aim of this study was to evaluate genetic and intrauterine environmental contributions to blood pressure (BP) and vascular functions in twins with discordant growth in utero. We studied 31 twin pairs (21 monozygous and nine dizygous), mean age 8 years) with large within-pair differences in birth weight. Among the monozygous pairs, nine had suffered from twin-to-twin-transfusion syndrome (TTTS). Apart from BP, we determined diameters and elasticity of the carotid artery and abdominal aorta with ultrasonography, and endothelial function in skin vessels with a laser Doppler technique, before and after transdermal delivery of acetylcholine and nitroglycerin. Eight of 62 twin subjects had a systolic BP above the 90th percentile in a North-American reference population. Among these, seven/eight were monozygous with a history of poor fetal growth and/or TTTS. In monozygous twin pairs without TTTS, systolic BP and pulse pressure were higher and vascular endothelial function was impaired in the lower birth weight twin. In the TTTS group, the lighter twin had a narrower carotid artery but there was no within-pair difference in arterial elasticity. Pre-eclampsia during the index pregnancy enhanced within-pair differences in BP but abolished within-pair differences in endothelial function. Severe fetal growth retardation contributes to higher BP, arterial narrowing and endothelial dysfunction in childhood. Pre-eclampsia may act both as an effect modifier and confounder of these associations.

Placental Dysfunction in Suramin-Treated Rats: Impact of Maternal Diabetes and Effects of Antioxidative Treatment

The aim of the present study was to evaluate a rat model of placental dysfunction/preeclampsia in pregnancies complicated by maternal diabetes. A second objective was to evaluate the effects of vitamin E treatment in this model. Normal and streptozotocin-induced diabetic rats of two different strains (U and H) were given intraperitoneal (IP) injections of the angiogenesis inhibitor Suramin (Sigma Chemical Co, St Louis, MO) or saline in early pregnancy, and fed standard or vitamin E-enriched food. The outcome of pregnancy was evaluated on gestational day 20. In both rat strains Suramin caused fetal growth retardation, decreased placental blood flow, and increased placental concentration of the isoprostane 8-iso-PGF(2alpha). In the U rats Suramin also caused increased fetal resorption rate, increased maternal blood pressure, decreased renal blood flow, and diminished maternal growth. Diabetes caused severe maternal and fetal growth retardation, increased resorption rate, and increased placental 8-iso-PGF(2alpha) concentration independent of Suramin administration. The maternal and fetal effects of Suramin and diabetes were more pronounced in the U strain than in the H strain. Vitamin E treatment improved the status of Suramin-injected diabetic rats: in U rats the blood pressure increase was normalized; and in both U and H rats the decreased placental blood flow was marginally enhanced, and the increase in placental 8-iso-PGF(2alpha) was partly normalized by vitamin E. Suramin injections to pregnant rats cause a state of placental insufficiency, which in U rats resembles human preeclampsia. The induction of this condition is at least partly mediated by oxidative stress, and antagonized by antioxidative treatment. Maternal diabetes involves increased oxidative stress, and causes both maternal and fetal morbidity, which are only marginally affected by additional Suramin treatment.

Prevention of pre-eclampsia by low-dose acetylsalicylic acid--a critical appraisal

Pre-eclampsia has been shown to be associated with platelet activation and excessive release of vasoconstricting thromboxane preceding the onset of the disease. Low-dose acetylsalicylic acid (ASA) substantially inhibits thromboxane formation and may thus prevent pre-eclampsia from developing. In agreement with this hypothesis early randomised trials reported on promising reductions in pre-eclampsia risk and possible fetal growth retardation. Subsequent multicentre trials during the nineties failed to confirm a large benefit, which may in part be explained by late initiation of treatment, low dosages, low patient compliance and wide inclusion of women with concomitant disorders such as chronic hypertension, diabetes mellitus and kidney disease. A recent systematic review of all randomised trials showed an acceptable safety profile and a significant but only moderate reduction in the risk of pre-eclampsia regardless of gestation at trial entry or dose of ASA. There is now growing evidence that the earlier ASA treatment is started, the greater the reduction in the risk of pre-eclampsia is. Moreover, ASA has much stronger effects at higher (80 - 150 mg/day) than at lower doses in the protection against pre-eclampsia and the prevention of severe fetal growth retardation. No clinically important effects, however, have been found in patients with chronic hypertension, kidney disease or diabetes mellitus. In contrast, low dose ASA (100 mg/day) might benefit women with unfavourable obstetric history, in particular those with severe fetal growth retardation or pre-eclampsia with onset at < 32 weeks. The crucial time for starting treatment may be before 16 weeks and daily ingestion before bedtime appears useful. To start low-dose ASA at 20 - 24 weeks gestation seems only justified in women with abnormal uterine Doppler flow.