Volume 45, Issue 7 - Hightlight: Intrauterine Growth Restriction and Preeclampsia

The means of fetal nutrition has been debated for over two millennia, with the controversy of oral versus parenteral nutrition already in the Corpus Hippocraticum . In 1587 Aranzio rejected connections between maternal and fetal blood vessels, and coined the term “hepar uterinum” for the placenta. From the 16th to the 18th century, a fervent debate focused on the type and extent of connection between maternal and fetal vessels, which was finally settled by Hunter’s injection experiment in 1774. But up to the middle of the 19th century, an important nutritive function was attributed to amniotic fluid. When with the discovery of oxygen the placenta’s respiratory function became understood, its nutritional function fell from grace. Most scientists realized reluctantly that the organ had numerous functions. As late as in the 19th century, the advent of microscopy allowed cell theory to develop, and analytical chemistry furthered the understanding of the transport of nutrients across the placenta. The identification of the syncytiotrophoblast made passive diffusion unlikely. Radioisotopes, molecular biology and the fluid mosaic model of the cell membrane revealed active transport mechanisms for nearly all macronutrients.

Childbearing age continues to rise and, with the increasing implementation of assisted reproductive technology (ART), the number of multiple pregnancies has also risen. This is a retrospective cohort study on maternal and neonatal outcomes of the twin pregnancies of 57 women aged ≥45 years compared to 114 younger women who gave birth in our institution between January 2011 and August 2015. Data were extracted from the real-time computerized database. The rates of hypertensive complications and pre-eclampsia (PE) were much higher in the study group compared to the controls (24/57 vs. 19/114, P=0.000 and 15/57 vs. 13/114, P=0.013, respectively). The respective incidence of very low birth weight (VLBW) was also significantly higher (14/114 vs. 12/228, P=0.021). Infants in the study group required four times more intubation and had a higher admission rate to the neonatal intensive care unit (NICU) compared to control infants (14/114 vs. 6/228 P=0.000 and 42/114 vs. 57/228, P=0.023, respectively). We conclude that women older than 45 years with twin pregnancies have higher maternal and perinatal complications with worse outcomes in comparison with younger women. When pregnancy is attempted via ART, embryo transfer of only one embryo should be considered in this age group.

Introduction: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are separate disease entities that have frequently been reported as sharing the same pathogenesis. In both of them, angiogenesis disorders and generalized endothelial damage with an accompanying inflammation are the dominant symptoms. In this study, we attempted to prove that both these processes demonstrate the same profile in early PE, late PE and IUGR patients, while the only difference is in the degree of exacerbation of the lesions. Patients, materials and methods: In 167 patients divided into four groups, three of those with early PE, late PE and IUGR and one control group, fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), high sensitive c-reactive protein (hsCRP) and fibronectin were determined. The behavior of these parameters in each of the groups was studied, and correlations between them were sought for. Results: Higher concentrations of sFlt-1, hsCRP and fibronectin and a lower concentration of PlGF were found in the study groups compared to the control group. Significant correlations were observed between the factors concerned. Conclusions: The higher values of disordered angiogenesis markers, endothelial damage markers and inflammatory markers both in the PE and the intrauterine growth restriction (IUGR) groups suggest the existence of shared disorders in the development of these pathologies. The correlations between disordered angiogenesis markers and endothelial damage markers argue in favor of a mutual relationship between these two processes in the development of pathologies evolving as secondary to placental ischemia. The results obtained confirm that the lesion profiles are the same in both PE and IUGR patients, which can be utilized in developing common diagnostic criteria.

Aim: Owing to its mysterious etiology, pathogenesis of preeclampsia (PE) remains controversial. Here we aimed to compare the levels of an angiogenesis marker, split and hairy related protein-1 (SHARP1), in PE vs. normal pregnancy. Methods: Thirty-one patients with early-onset PE (EOPE), 26 patients with late-onset PE (LOPE), and 33 patients as a control group were recruited for this study in a tertiary referral center in Ankara, Turkey. Maternal venous SHARP1 levels and individual characteristics of the three groups were compared. Results: Age and body mass indices were similar among the three groups. SHARP1 levels in patients with PE (27.7±13.2 ng/mL) were significantly lower than in the control group (34.7±17 ng/mL) (P=0.006). Additionally, SHARP1 levels were significantly different among patients in EOPE, LOPE, and control groups (P=0.022). Birth weights and Apgar scores in patients in EOPE group were significantly lower than the other two groups and showed a gradual increase from the EOPE group to the LOPE and the control group. Binary logistic regression method demonstrated that maternal venous SHARP1 level was a risk factor for PE. Conclusions: Maternal venous SHARP1 levels in PE are lower than a normal pregnancy. Its clinical applicability and role as a candidate for making sense of the distinctive pathogenesis of the EOPE and LOPE remain to be elucidated.

Aim: To determine whether late second-trimester maternal serum biomarkers are useful for the prediction of preeclampsia during the third trimester, a case-control study including 33 preeclamptic and 71 healthy pregnancies was conducted. Maternal serum concentrations of placental protein 13 (PP13), pregnancy-associated plasma protein (PAPP-A), pentraxin3 (PTX3), soluble FMS-like tyrosine kinase-1 (sFlt-1), myostatin and follistatin-like-3 (FSLT-3) were measured at 24–28 weeks’ gestation. All the concentrations of these markers were compared between the preeclamptic and control groups. Receiver operating characteristic (ROC) curve analysis was applied to assess sensitivity and specificity of serum markers with significant difference. Results: The levels of PP13 and sFlt-1 were significantly increased and FSLT3 was significantly decreased in patients with preeclampsia. However, the concentration of PAPPA, PTX3 and myostatin did not differ significantly. In screening for preeclampsia during the third trimester by PP13, sFlt-1 and FSLT3, the detection rate was 61.3%, 48.1% and 39.1%, respectively, at 80% specificity, and the detection rate increased to 69.8% by combination of these three markers. Conclusion: Maternal serum levels of PP13, sFlt-1 and FSLT3 play an important role in predicting late-onset preeclampsia, and the combination of these three markers significantly increases the detection rate for prediction.

Aim: The aim of this study was to evaluate the predictive value of α-fetoprotein in maternal serum (MS-AFP) as a marker for diverse pregnancy outcomes. Methods: The study was based on pregnancy and delivery data from 5520 women between 1999 and 2014 at University Hospital of Zurich (UHZ). Inclusion criteria: both MS-AFP and pregnancy outcome were known for the same pregnancy. Pregnancy outcomes and characteristics such as fetal malformation, intrauterine fetal death (IUFD) and intrauterine growth retardation as well as maternal age, weight before pregnancy, gestational age (GA) at delivery, newborn weight, length and head circumference were analyzed with respect to the MS-AFP value. MS-AFP value was categorized into three groups: elevated MS-AFP>2.5 multiples of the median (MoM), normal 0.5–2.49 MoM and decreased <0.5 MoM. Results: Newborn weight (g) and length (cm) were significantly lower in the elevated MS-AFP (P<0.001) group, and infants had 1 week lower GA at delivery (P<0.05). In the group of elevated MS-AFP (n=46), 26.1% of pregnancies were significantly related to adverse pregnancy outcomes, such as fetal malformations, fetuses small for gestational age (SGA) and IUFD. Adverse pregnancy outcomes of 5.6% were registered in the group of normal MS-AFP and 7.3% in the group of low MS-AFP (P<0.05). Conclusion: MS-AFP level in the second trimester is still an important indicator of fetal surface malformations; however, ultrasound still outweighs as a screening method. Nevertheless, pregnant women with elevated MS-AFP values and with no sonographically detected fetal malformations should additionally receive the third trimester ultrasound examination to exclude other possible complications of pregnancy.

Purpose: To evaluate longitudinal mechanical dyssynchrony in normally grown fetuses by speckle tracking echocardiography (STE) and to compare longitudinal mechanical dyssynchrony in fetal growth restriction (FGR) with normal controls. Materials and methods: A prospective study was performed on 30 FGR and 62 normally grown fetuses, including 30 controls matched by gestational age, using STE and a transversal four-chamber view. Data analysis was carried out with a high frame rate of about 175 frames/s. Dyssynchrony was analyzed offline with QLab 9 (Philips Medical Systems, Andover, MA, USA) as time differences between peaks in strain of both ventricles and the septum. Inter- and intraventricular and intraseptal dyssynchrony were obtained and inter- and intraobserver reliability was analyzed. Results: Longitudinal mechanical dyssynchrony was feasible in all cases, with high inter- and intraobserver reliability. Levels of inter- and intraventricular dyssynchrony were higher in the FGR than in the control group. Conclusion: Speckle tracking echocardiography (STE) is a reliable technique for cardiac function assessment in the fetal heart. Interventricular dyssynchrony could be a potential parameter for early detection of subclinical myocardial dysfunction before other parameters demand intervention. The future clinical role of longitudinal mechanical dyssynchrony needs to be verified in larger studies and with a technique customized for prenatal echocardiography.

Aim: Intrauterine growth restriction (IUGR) is an independent risk factor for the development of cardiovascular diseases later in life. The mechanisms whereby slowed intrauterine growth confers vascular risk are not clearly established. In general, a disturbed cholesterol efflux has been linked to atherosclerosis. The capacity of serum to accept cholesterol has been repeatedly evaluated in clinical studies by the use of macrophage-based cholesterol efflux assays and, if disturbed, precedes atherosclerotic diseases years before the clinical diagnosis. We now hypothesized that circulating cholesterol acceptors in IUGR sera specifically interfere with cholesterol transport mechanisms leading to diminished cholesterol efflux. Methods: RAW264.7 cells were used to determine efflux of [ 3 H]-cholesterol in response to [umbilical cord serum (IUGR), n=20; controls (CTRL), n=20]. Results: Cholesterol efflux was lower in IUGR as compared to controls [controls: mean 7.7% fractional [ 3 H]-cholesterol efflux, standard deviation (SD)=0.98; IUGR: mean 6.3%, SD=0.79; P<0.0001]. Values strongly correlated to HDL (ρ=0.655, P<0.0001) and apoE (ρ=0.510, P=0.0008), and mildly to apoA1 (ρ=0.3926, P=0.0122) concentrations. Conclusions: Reduced cholesterol efflux in IUGR could account for the enhanced risk of developing cardiovascular diseases later in life.

Aims: Severe preterm fetal growth restriction (FGR) remote from term is problematic. We aimed to investigate the effect of maternally-administered antithrombin on maternal and neonatal outcomes. A prospective, one-arm, pilot study was performed in 14 women with severe FGR (≤5 th centile) at <28 weeks of gestation, without hypertensive disorders. Maternal plasma concentrations of soluble Feline McDonough Sarcoma (FMS)-like trypsin kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured and categorized into three groups: group 1; low sFlt-1 and high PlGF, group 2; moderate sFlt-1 and low PlGF, and group 3; high sFlt-1 and low PlGF. Antithrombin was administered for 3 days. The incidence of perinatal mortality, infant morbidity, and the period of pregnancy prolongation were compared. Results: In group 1 (n=4), their pregnancies were extended for longer periods and the maternal and infant outcomes were good. The prolongation periods were shorter in groups 2 (n=3) and 3 (n=7), which resulted in poor maternal [severe preeclampsia or hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome] and infant outcomes. Conclusions: The evaluation of the maternal sFlt-1 and PlGF at 21–27 weeks of gestation is useful in the managements of severe FGR. Antithrombin treatment could prolong the pregnancies with low sFlt-1 and high PlGF without negatively affecting maternal or fetal health.

Aim: To propose a simple model for predicting preeclampsia (PE) in the 1 st trimester of pregnancy on the basis of maternal characteristics (MC) and mean arterial pressure (MAP). Methods: A prospective cohort was performed to predict PE between 11 and 13+6 weeks of gestation. The MC evaluated were maternal age, skin color, parity, previous PE, smoking, family history of PE, hypertension, diabetes mellitus and body mass index (BMI). Mean arterial blood pressure (MAP) was measured at the time of the 1 st trimester ultrasound. The outcome measures were the incidences of total PE, preterm PE (delivery <37 weeks) and term PE (delivery ≥37 weeks). We performed logistic regression analysis to determine which factors made significant contributions for the prediction of the three outcomes. Results: We analyzed 733 pregnant women; 55 developed PE, 21 of those developed preterm PE and 34 term PE. For total PE, the best model was MC+MAP, which had an area under the receiver operating characteristic curve (AUC ROC) of 0.79 [95% confidence interval (CI)=0.76–0.82]. For preterm PE, the best model was MC+MAP, with an AUC ROC of 0.84 (95% CI=0.81–0.87). For term PE, the best model was MC, with an AUC ROC of 0.75 (0.72–0.79). The MC+MAP model demonstrated a detection rate of 67% cases of preterm PE, with a false-positive rate of 10%, positive predictive value of 17% and negative predictive value of 99%. Conclusion: The MC+MAP model showed good accuracy in predicting preterm PE in the 1 st trimester of gestation.

Objective: The aim of this study was to determine the association between chronic placental inflammation and amniotic fluid (AF) markers of maternal anti-fetal rejection as well as the presence of microorganisms in the AF fluid of patients with fetal death. Study Design: This cohort study included 40 patients with fetal death whose placentas were examined for chronic inflammatory lesions and whose AF chemokine ligand (CXCL)10 and interleukin (IL)-6 concentrations were determined by immunoassays. AF was processed for bacteria, mycoplasmas and viruses using cultivation and molecular microbiologic techniques (i.e. PCR-ESI/MS). Results: (1) The most prevalent placental findings were maternal vascular underperfusion (63.2%, 24/38), followed by chronic inflammatory lesions (57.9%, 22/38); (2) chronic chorioamnionitis (18/38) was three times more frequent than villitis of unknown etiology (6/38); (3) an elevated AF CXCL10 concentration (above the 95 th centile) was present in 60% of the cases, and a receiver operating characteristics (ROC)-derived cut-off of 2.9 ng/mL had a sensitivity of 73% and a specificity of 75% in the identification of chronic placental inflammatory lesions; (4) only five cases had microbial invasion of the amniotic cavity, and the presence of microorganisms did not correlate with chronic placental inflammation. Conclusion: In women with unexplained fetal death, there is an association between elevated AF CXCL10 and chronic placental inflammatory lesions. Therefore, we conclude that a subset of patients with fetal death may have endured a breakdown of maternal-fetal tolerance, which cannot be attributed to microorganisms in the amniotic cavity.

Objective: To evaluate placental gene expression in severe early- or late-onset preeclampsia with intrauterine growth restriction compared to controls. Study design: Chorionic villus sampling was conducted after cesarean section from the placentas of five women with early- or late-onset severe preeclampsia and five controls for each preeclampsia group. Microarray analysis was performed to identify gene expression differences between the groups. Results: Pathway analysis showed over-representation of gene ontology (GO) biological process terms related to inflammatory and immune response pathways, platelet development, vascular development, female pregnancy and reproduction in early-onset preeclampsia. Pathways related to immunity, complement and coagulation cascade were overrepresented in the hypergeometric test for the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Ten genes ( ABI3BP, C7, HLA-G, IL2RB, KRBOX1, LRRC15, METTL7B, MPP5, RFLNB and SLC20A ) had a ≥±1 fold expression difference in severe early-onset preeclampsia group compared to early controls. There were 362 genes that had a ≥±1 fold expression difference in severe early-onset preeclampsia group compared to late-onset preeclampsia group including ABI3BP , C7, HLA-G and IL2RB . Conclusion: There are significant differences in placental gene expression between severe early- and late-onset preeclampsia when both are associated with intrauterine growth restriction. ABI3BP , C7, HLA-G and IL2RB might contribute to the development of early form of severe preeclampsia.

Aim: To investigate both maternal and umbilical cord adropin levels in patients with preeclampsia and the possible relations with its severity and perinatal outcomes. Materials and methods: In this study, a total of 38 preeclamptic and 40 age-matched healthy pregnant women between January and June 2016 were included. Serum and cord adropin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results: The maternal and umbilical cord adropin levels were significantly lower in the preeclamptic group compared to controls [71.19±22.21 vs. 100.76±27.02 ng/L and 92.39 (59.77:129.89) vs. 106.20 (74.42:208.02) ng/L, P<0.001, respectively]. While maternal adropin levels were significantly lower in the severe preeclampsia group as compared to the mild preeclamptic group [66.45 (21.49:98.02) vs. 76.17 (58.06:109.58), P=0.007], umbilical cord adropin levels did not differ between each group [91.32 (59.77:113.34) vs. 92.87 (63.12:129.89), P=0.750]. Maternal adropin level was negatively correlated with systolic and diastolic blood pressures (r=−0.60, P<0.001 and r=−0.58, P<0.001, respectively) and positively correlated with platelet count (r=0.27, P=0.016). Moreover, umbilical cord adropin levels were weakly correlated with gestational age at delivery (r=0.28, P=0.012) and birth weight (r=0.28, P=0.014). Conclusion: The present study is the first to demonstrate a significant association between maternal and umbilical adropin levels and the presence and severity of preeclampsia. Adropin might be a useful parameter for predicting the presence and severity of preeclampsia.

The placenta is the principal organ regulating respiratory, nutritional, endocrine and metabolic functions on behalf of the developing fetus. Changes in gene expression patterns of placenta-specific genes may influence fetal growth. We profiled the expression of 17 genes related to placenta functioning in term placentas (n=677) to identify genes differentially expressed across birth weight categories [small (SGA), appropriate (AGA) and large (LGA) for gestational age]. ABCG2, CEBPB, CRH, GCM1, GPC3, INSL4, PGF and PLAC1 were inversely associated with LGA status, with odds ratios (ORs) and 95% confidence intervals (CI) ranging from GCM1 (OR=0.44, 95% CI: 0.29, 0.70) to CRH (OR=0.73, 95% CI: 0.61, 0.88). NR3C1 was positively associated with LGA status (OR=2.33, 95% CI: 1.43, 3.78). PLAC1 (OR=0.66, 95% CI: 0.47, 0.92) and ABCG2 (OR=0.63, 95% CI: 0.44, 0.91) were additionally inversely associated with SGA status, and PGF was positively associated with SGA status (OR=1.59, 95% CI=1.08, 2.35). General trends were confirmed in an independent cohort (n=306). Given that aberrant fetal growth may have long-lasting effects, our results suggest the potential utility of placental gene expression profiles as potential early markers of disease onset later in life.

Introduction: Circulating soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are potential markers for preeclampsia. The objective was to construct and analyse the reference ranges of serum levels of sFlt-1 and PlGF throughout the course of pregnancy in low-risk Thai pregnant women. Methods: We enrolled 110 low-risk, Thai women singleton pregnancy from 10 to 40 gestational weeks. Serum concentrations of sFlt-1 and PlGF were measured with an automated assay. The reference ranges of serum levels of sFlt-1, PlGF and sFlt-1/PlGF ratio were constructed and assessed for possible correlations with gestational age, maternal factors [age, parity, tobacco use, artificial reproductive technologies (ARTS) and body mass index (BMI)], and pregnancy outcomes (gestational age at delivery, development of preeclampsia, neonatal birth weight and placental weight). Results: None of the subjects developed preeclampsia. Serum sFlt-1 concentrations significantly elevated from 20 to 40 gestational weeks (P=0.003). Significant elevation and dropping of serum PlGF levels and sFlt-1/PlGF ratios were observed at 10 to 29 and 30 to 40 weeks of gestation, respectively (P<0.001). There was an inversed correlation between serum PlGF levels at 20 to 29 gestational weeks and neonatal birth weights (r=−0.48, P<0.05). There were no associations between serum levels of sFlt-1, PlGF, or sFlt-1/PlGF ratios and maternal BMI, gestational age at delivery, or placental weight (P>0.05). Effects from parity, smoking and ARTS were inconclusive. Conclusion: Robust change of serum PlGF levels suggests for its broader clinical application compared to sFlt-1. Prediction of preeclampsia using serum analytes may be gestational period specific.

Eclampsia remains one of the five major causes of maternal mortality in developing countries. Advances in diagnosis and management have led to a significant reduction in maternal mortality and morbidity from this disease in developed countries. In developing countries the incidence of maternal death attributed to eclampsia remains high and, in Ethiopia, maternal mortality from this complication has instead risen over the last decade. The purpose of this study was to review the incidence of eclampsia at the largest feto-maternal center in the country over 1 year in an attempt to determine what quality improvement measures are needed and could realistically be implemented within the system to decrease this complication. There were a total of 104 eclamptic patients during the study period. The hospital incidence of eclampsia was 82/10,000 deliveries excluding those arriving to the hospital in the postpartum period (28 cases). There were eight maternal deaths making the case fatality rate one in 13 cases. The median convulsion to arrival time, referral to arrival time and magnesium sulphate administration time were found to be 3, 2 and 3 h, respectively. The probability of multiple seizures (≥3 episodes) was increased significantly with the prolongation of these time variables. Occurrence of multiple seizures was in turn significantly associated with adverse maternal outcomes (ICU admission, morbidities and mortalities). As expected, there was a high incidence of eclampsia and eclampsia related maternal death in the hospital. We recommend a thorough assessment of the referral system, upgrading and capacity building of more health facilities, organizing trainings and drills in health facilities; and availing magnesium sulphate in all health centers among others.