Placental gene expression of the placental growth factor (PlGF) in intrauterine growth restriction

Objective: We analyzed changes in gene expression of placental growth factor (PIGF) in human placental samples obtained postpartum from pregnancies with IUGR.

Methods: During a twelve-month study period representing the calendar year of 2012 placental samples from 101 pregnancies with IUGR and from 140 normal pregnancies were obtained for analysis of a potential difference in PIGF gene expression.

Results: There was no significant difference in gene activity of the PIGF gene between the IUGR versus normal pregnancy groups (Ln2^α: 0.92; p?α: 0.72; p?=?0.05). Placental PIGF gene activity was significantly lower in fetuses with more severe IUGR versus less severe cases (Ln2^α: ?1.49; p?Conclusion: We found no difference in gene expression of PIGF in placental samples obtained from IUGR pregnancies versus normal pregnancy suggesting the absence of a direct role of PIGF gene activity in the development of defective angiogenesis in IUGR during the later stages of gestation. However, in more severe cases of intrauterine growth restriction PIGF expression does show a significant decrease indicating its potential role in the profound defect in angiogenesis in these cases.     

Cotyledonary-like placenta associated with severe intrauterine growth restriction

There have been no previous reports of human placentas mimicking the cotyledonary placenta of ruminants. We report a case of cotyledonary-like placenta associated with severe intrauterine growth restriction. A woman pregnant for the first time was referred to our hospital at 27 weeks' gestation because of severe intrauterine growth restriction. Characteristics of the placenta in the patient were examined by ultrasonographical and histopathological techniques. Ultrasonography revealed that a hypo-echoic area intermingled with small segmented tissues in the placenta. The hypo-echoic area changed in size and shape according to uterine contractions. At 31 weeks' gestation, a caesarean section was performed because of non-reassuring fetal status. A female baby weighing 814 g was delivered. The placenta, which weighed 260 g, contained several long stem villi running over a distance of 6 to 7 cm without branching into intermediate or terminal villi. Small villous tissues had developed only at the tips of these stem villi. The present case shows an extraordinarily abnormal development of the villous trees in the placenta, which may have caused fetal IUGR and non-reassuring fetal status.     

Placental gene expression patterns of epidermal growth factor in intrauterine growth restriction

Objective

In this study, we compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control.

Study design

Gene expression of EGF was determined from human placental samples collected from all pregnancies presenting with IUGR at our institution during the study period January 1, 2010–January 1, 2011. Multiple clinical variables were also assessed including maternal age, gestational weight gain, increase of BMI during pregnancy and fetal gender.

Results

A total of 241 samples were obtained (101 in the IUGR pregnancy group, 140 in the normal pregnancy group). EGF was found to be underexpressed in the IUGR group compared to normal pregnancy (Ln2^α: −1.54; p < 0.04). Within the IUGR group no fetal gender-dependent difference was seen in EGF gene expression (Ln2^α: 0.44; p < 0.06). Similarly, no significant difference in EGF expression was noted in cases with more vs. less severe forms of IUGR (Ln2^α: −0.08; p = 0.05). IUGR pregnancies were significantly more common in the maternal age group 35–44 years compared to other age groups. Gestational weight gain and gestational BMI increase were significantly lower in IUGR pregnancies compared to controls.

Conclusions

Placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy.     

Placental characteristics in monochorionic twins with selective intrauterine growth restriction assessed by gradient angiography and three-dimensional reconstruction

Objective: To investigate the placental characteristics in selective intrauterine growth restriction (sIUGR) using gradient angiography and three-dimensional (3D) reconstruction from computed tomography (CT) scan data.

Methods: This study included 23 sIUGR cases and 16 monochorionic twin-pregnancies without sIUGR. We injected nonionic iodinated contrast agents into the umbilical arteries and veins. Placental characteristics were analyzed after CT scanning and 3D reconstruction.

Results: 73.9% of smaller twins in sIUGR cases had marginal or velamentous cord insertions and less placental sharing. The terminal branch of the arterial tree was scored III–IV in smaller sIUGR twins, while it was scored V–VII in normal monochorionic twins and larger sIUGR twins. Arterio-arterial (A-A) anastomoses presented in all monochorionic placentas. Veno-venous (V-V) anastomoses present in 83.3% (5/6) of Type III sIUGR cases, which was higher than observed in Type I–II cases. The mean diameters of A-A and V-V anastomoses were larger in Type III sIUGR cases.

Conclusions: Gradient angiography and 3D placental models displayed different placental angioarchitectures and voluminal placental sharing among three types of sIUGR cases. Placental dysplasia in the smaller twin may cause abnormal cord insertion and unequal placental sharing. The inter-twin anatomoses influence the umbilical cord artery (UA) Doppler and natural pathogenesis of sIUGR.     

Non-placental causes of intrauterine growth restriction

Placental insufficiency, in some form or fashion, is associated with the majority of cases of intrauterine growth restriction (IUGR). There are numerous causes of IUGR which are not caused primarily by placental insufficiency, but indirectly lead to it. The causes of IUGR can be subdivided into fetal and maternal etiologies. The fetal etiologies consist of genetic diseases, congenital malformations, infections, multiple gestations, and placental/cord abnormalities. The maternal etiologies are categorized as follows: (1) decreased uteroplacental blood flow, (2) reduced blood volume, (3) decreased oxygen carrying capacity, (4) nutrition status, (5) teratogens, and (6) miscellaneous causes such as short interpregnancy intervals, race, maternal age, and low socioeconomic status. Knowledge of the etiologies of fetal growth restriction is essential, so that future care can be targeted at prevention. There are several primary and secondary prevention strategies that can be adopted.     

Placental gene expression of transforming growth factor beta 1 (TGF-β1) in small for gestational age newborns

Objective: The gene expression of transforming growth factor beta-1 (TGF-β1) in human placental samples obtained from pregnancies with small for gestational age fetuses (SGA) was compared to those of normal pregnancies.

Methods: In 2011 placental samples from 101 pregnancies with SGA and from 140 normal pregnancies were obtained for analysis of TGF-β1 gene expression. Several clinical parameters were also assessed for correlation between genetic and clinical parameters.

Results: There were no significant differences in gene activity of the TGF-β1 gene between the SGA versus normal pregnancy groups (Ln2^α: 0.16; p?=?0.07). Within the SGA group, no fetal gender-dependent differences were seen in TGF-β1 gene expression (Ln2^α: ?0.11; p?=?0.05). Similarly, no significant differences in gene activity were observed by the degree of severity of SGA as assessed by percentile fetal birth-weight (Ln2^α: 0.32; p?=?0.06).

Conclusion: We found no change in gene expression of TGF-β1 in placental samples obtained from SGA pregnancies versus normal pregnancy suggesting an absence of a direct role of the TGF-β1 gene in the development of SGA. However, the absence of increased gene expression of TGF-β1 in SGA can be conceptualized as a failure to mount a compensatory response in the SGA environment.     

Placental ratio in pregnancies at different risk for intrauterine growth

Objective: We have analyzed the placental/birthweight ratio in women at increased risk of intrauterine growth retardation and pregnancy-induced hypertension and in women with pregnancy ‘complicated’ by these conditions. Study design: A total of 89 women with small gestational age (SGA) infants, 355 with appropriate gestational age infants (200 in the uncomplicated pregnancy group) and 28 with large for gestational age (LGA) infants were considered. Results and Conclusion: The mean placental weight showed a significant increase from the SGA to the LGA in the two groups. The placental ratio tended to increase from the LGA group to the SGA one both in infants of women with uncomplicated pregnancy and with pregnancy complicated by intrauterine growth retardation or pregnancy-induced hypertension; these findings were statistically significant.     

Increased placental apoptosis in intrauterine growth restriction

OBJECTIVES: Our purpose was to investigate a possible role for apoptosis in the pathophysiologic mechanisms of intrauterine growth restriction. STUDY DESIGN: Placental samples were obtained from 43 uncomplicated third-trimester pregnancies and from 26 pregnancies complicated by intrauterine growth restriction. The definition used to identify cases of intrauterine growth restriction depended on three criteria: clinical evidence of suboptimal growth, ultrasonographic evidence of deviation from an appropriate growth percentile, and individualized birth weight ratios <10th percentile. Light microscopy was used to quantify the incidence of apoptosis. Electron microscopy and TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling) staining were used to confirm the occurrence of apoptosis. RESULTS: Quantification of apoptosis (medians and interquartile ranges) resulted in the following values: normal third trimester (n = 43) 0.14% of cells (0.08% to 0.20%) and intrauterine growth restriction third trimester (n  = 26) 0.24% of cells (0.16% to 0.29%). The incidence of apoptosis was significantly higher in placentas from pregnancies with intrauterine growth restriction compared with normal third-trimester placentas (p < 0.01, Mann Whitney U test). CONCLUSIONS: These results suggest that apoptosis may play a role in the pathophysiologic mechanisms of intrauterine growth restriction.(Am J Obstet Gynecol 1997;177:401)     

The prognostic value of endoglin (CD105) expression in ovarian carcinoma

Intratumoral angiogenesis has become an important issue after the identification of antiangiogenic therapeutics. The purpose of this study was to investigate the prognostic value of CD105 in patients with ovarian cancer and also to compare with CD31. Fifty-eight patients were included to this study. All the paraffin blocks were reviewed, and angiogenesis was determined by immunohistochemical staining, using anti-CD105 and anti-CD31 monoclonal antibodies. The mean microvessel density (MVD) with CD105 and CD31 were 28.78 +/- 22.20 and 28.69 +/- 18.57, respectively (P = 0.97). With respect to prognostic factors, CD31 was only significant for suboptimal cytoreduction (P = 0.02), and CD105 was significant for both advanced stage and suboptimal cytoreduction (P = 0.02 and P = 0.05, respectively). For survival analysis, patients were divided into three groups by quartiles for each marker (group 1, <25%; group 2, 25-75%; and group 3, >75%). By CD31, only significant difference was noted between group 1 and group 2 (P = 0.03). In analysis with CD105, the survival rate of patients with group 3 was significantly worse than group 1 and group 2 (P = 0.01 for both). In multivariate analysis, cytoreduction and MVD determined by CD105 remained significant. In this study, endoglin was found to be an independent predictor of poor survival. Therefore, it could be used for antiangiogenic therapies.     

Molecular mechanisms of intrauterine growth restriction

Intrauterine growth restriction (IUGR) is a pregnancy specific disease characterized by decreased growth rate of fetus than the normal growth potential at particular gestational age. In the current scenario it is a leading cause of fetal and neonatal morbidity and mortality. In the last decade exhilarating experimental studies from several laboratories have provided fascinating proof for comprehension of molecular basis of IUGR. Atypical expression of enzymes governed by TGFβ causes the placental apoptosis and altered expression of TGFβ due to hyper alimentation causes impairment of lung function. Crosstalk of cAMP with protein kinases plays a prominent role in the regulation of cortisol levels. Increasing levels of NOD1 proteins leads to development of IUGR by increasing the levels of inflammatory mediators. Increase in leptin synthesis in placental trophoblast cells is associated with IUGR. In this review, we emphasize on the regulatory mechanisms of IUGR and its associated diseases. They may help improve the in-utero fetal growth and provide a better therapeutic intervention for prevention and treatment of IUGR.     

An animal model of placental insufficiency-induced intrauterine growth restriction

Intrauterine growth restriction (IUGR), often associated with functional placental insufficiency, results in increased perinatal mortality and morbidity. For obvious reasons, many questions regarding the progression of IUGR pregnancies cannot be addressed experimentally in humans, predicating the use of animal models. Although no animal model fully recapitulates human pregnancy, the pregnant sheep has been used extensively to investigate maternal-fetal interactions. In sheep, surgical placement of catheters in both the maternal and fetal vasculature allows repeated sampling from nonanesthetized pregnancies. Considerable insight has been gained on placental oxygen and nutrient transfer and utilization from use of pregnant sheep, often confirmed in the human once appropriate technologies became available. This review will focus on one sheep model, used to examine the impact of placental insufficiency-induced IUGR on oxygen and nutrient transport and utilization.     

Angiogenic factors for prediction of preeclampsia and intrauterine growth restriction onset in high-risk women: AngioPred study

Objective: The study aimed to compare the level of two angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), for the prediction of preeclampsia and intrauterine growth restriction in high-risk pregnant women.

Methods: A prospective multicenter cohort study of 200 pregnant patients was conducted between June 2008 and October 2010. sFlt1 and sEng were measured by enzyme-linked immunosorbent assay.

Results: Forty-five patients developed a placenta-mediated adverse pregnancy outcome. Plasma levels of sFlt1 and sEng were higher in patients who will experience a preeclampsia at 28, 32, and 36 weeks compared with patients with no complication. The same results were observed for intrauterine growth restriction. Plasma levels of sFlt1 and sEng were not significantly different for patients with preeclampsia compare to patients with intrauterine growth restriction. Patients with early pre-eclampsia (PE) had very high rates of angiogenic factors at 20, 24, and 28 weeks. Patients with late PE and early and late intrauterine growth retardation (IUGR) had high rates at 32 and 36 weeks.

Conclusion: In high-risk women, angiogenic factors are disturbed before the onset of preeclampsia and this is true for intrauterine growth restriction.     

Isolated intrauterine growth restriction: a survey of Central Association of Obstetricians Gynecologists (CAOG) members

Objective: The objective was to ascertain clinicians’ opinions and current management with isolated (no concomitant morbidity) intrauterine growth restriction (IUGR). Methods: Members of the Central Association of Obstetricians and Gynecologists (CAOG) were surveyed. We considered consensus to be agreement among 90% of the respondents. Results: The response rate was 36% (137/385). Among the 21 questions on the topic, the only consensus was that none of the respondents informed women of the recurrence rate of IUGR. There was variance in what constitutes IUGR as well as practice patterns for detection and management of suboptimal growth. Ten (7%) of the respondents had at least one litigation involving management of IUGR. Responses from 87 general obstetrician-gynecologists varied significantly from that of 33 maternal-fetal medicine (MFM) subspecialists for 48% (10/21) of the survey questions (p < 0.05). Conclusions: There is large practice variation in detection and management of isolated IUGR. This stresses the need for additional studies and a national guideline on its management.     

Preeclampsia in twin pregnancies: association with selective intrauterine growth restriction

Objective: To identify the association between preeclampsia (PE) and selective intrauterine growth restriction (sIUGR) in twin pregnancies.

Methods: This was a retrospective cohort study of 1004 twin pregnancies from 2008 to 2014. We specifically compared the incidence, clinical characteristics and outcomes of PE between sIUGR and normal-growth twin pregnancies.

Results: PE occurred more frequently in sIUGR pregnancies [29.0% (51/176)] than in normal-growth twin pregnancies [13.1% (99/756), p?<?0.001, adjusted odds ratio 3.29]. Among sIUGR, the incidence of PE was significantly higher in dichorionic (DC) pregnancies (37.5%, 30/80) than in monochorionic (MC) pregnancies (21.9%, 21/96). The rates of onset at <32 weeks (p?=?0.045) and of severe PE (p?=?0.025) were higher in sIUGR pregnancies with PE. The systolic blood pressure was also higher in sIUGR pregnancies with PE (152.6?±?11.8?mmHg) than in normal-growth pregnancies with PE (148.0?±?8.2?mmHg) (p?=?0.042). Additionally, more sIUGR pregnancies were delivered at 32–36 weeks (p?=?0.001), and fewer were delivered at ≥36 weeks (p?<?0.001). Moreover, the prevalence of severe neonatal asphyxia was higher in sIUGR pregnancies with PE than in normal-growth pregnancies with PE (8.8% versus 2.5%, p?=?0.020).

Conclusions: sIUGR is associated with increased odds of developing severe PE in twin pregnancies, leading to poorer perinatal outcomes.