Reduction of maternal circulating endothelial progenitor cells in human pregnancies with intrauterine growth restriction

Introduction

Circulating endothelial progenitor cells (EPCs) may play a crucial role during pregnancy by sustaining adequate placentation and fetal growth. Unambiguous demonstration of EPC increase during pregnancy has been hampered so far by lack of standardized methods for EPC quantification. In this study we used the currently most accepted phenotype for EPC detection for investigating whether maternal circulating EPCs might increase during normal pregnancy and whether they may fail to increase in pregnancy complicated by idiopathic intrauterine growth restriction (IUGR), a leading cause of perinatal mortality and morbidity characterized by insufficient placental perfusion.

Methods

Twenty-one non-pregnant women, 44 women during healthy pregnancy progression (9, 13 and 22 women in the first, second and third trimester, respectively) and 11 with pregnancy complicated by idiopathic IUGR were recruited in a cross-sectional study. EPCs in maternal blood were identified as CD45^dim/CD34⁺/KDR⁺ cells by flow cytometry. Plasmatic cytokines were measured by ELISA.

Results

We observed a significant and progressive increase of EPCs in normal pregnancy, yet detectable in early pregnancy but even more pronounced in the third trimester. The increase of EPCs was impaired in IUGR-complicated pregnancies at comparable gestational age. The circulating levels of placental growth-factor and stromal-derived-factor-1 were significantly lower in IUGR than normal pregnancies, possibly contributing to EPC impairment.

Conclusions

EPC count in maternal circulation may have a great potential as a novel biomarker for pregnancy monitoring and may represent the target of novel therapeutic strategies designed to prevent adverse pregnancy outcomes often occurring in IUGR.     

Placental pathology in fetal growth restriction

Objectives

One of the causes of intrauterine fetal growth restriction (FGR) can be pathology of the placenta. The aim of this study was to compare macroscopic and microscopic changes of the placentas from intrauterine growth restricted fetuses with those from normally developed fetuses, in order to test the hypothesis that vascular damage due to decreased maternal vascular perfusion may be responsible for FGR.

Study design

Between May 2007 and December 2008 we performed detailed macroscopic and histological examination of singleton placentas of 50 consecutive neonates with fetal growth restriction (FGR group) and compared them to 50 normal fetuses, born next to an FGR case, as a control group.

Results

Gestational age, birth weight, spontaneous delivery rate, mean weight of the placenta and the fetal-placental weight ratio were all lower in the FGR group than in the control group (p < 0.05). Thickening of the villous trophoblastic basal membrane, incidence of villous infarction, presence of thrombi or haematomas and the incidence of villitis were more common in the FGR group than in the controls (p < 0.05). There were, however, no significant differences in perivillous fibrin deposition, stromal fibrosis and cytotrophoblast proliferation between the groups. In FGR women who smoked, intervillous haematomas and villous infarction were more common (p < 0.05) than in controls.

Conclusions

All macroscopic and microscopic pathological changes associated with FGR were directly linked to reduction of placental blood flow. As smoking is a main risk factor for these placental abnormalities these results emphasize the need to persuade women to quit smoking not only during pregnancy, but even better long before pregnancy.     

Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction

IntroductionDiscriminating between placentally-mediated fetal growth restriction and constitutionally-small fetuses is a challenge in obstetric practice. Placental growth factor (PlGF), measurable in the maternal circulation, may have this discriminatory capacity.MethodsPlasma PlGF was measured in women presenting with suspected fetal growth restriction (FGR; ultrasound fetal abdominal circumference <10th percentile for gestational age) at sites in Canada, New Zealand and the United Kingdom. When available, placenta tissue underwent histopathological examination for lesions indicating placental dysfunction, blinded to PlGF and clinical outcome. Lesions were evaluated according to pre-specified severity criteria and an overall severity grade was assigned (0–3, absent to severe). Low PlGF (concentration <5th percentile for gestational age) to identify placental FGR (severity grade ≥ 2) was assessed and compared with routine parameters for fetal assessment. For all cases, the relationship between PlGF and the sampling-to-delivery interval was determined.ResultsLow PlGF identified placental FGR with an area under the receiver-operator characteristic curve of 0.96 [95% CI 0.93–0.98], 98.2% [95% CI 90.5–99.9] sensitivity and 75.1% [95% CI 67.6–81.7] specificity. Negative and positive predictive values were 99.2% [95% CI 95.4–99.9] and 58.5% [95% CI 47.9–68.6], respectively. Low PlGF outperformed gestational age, abdominal circumference and umbilical artery resistance index in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, P < 0.0001).DiscussionLow PlGF identifies small fetuses with significant underlying placental pathology and is a promising tool for antenatal discrimination of FGR from fetuses who are constitutionally-small.     

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.     

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.     

Reduced maternal serum concentrations of angiopoietin-2 in the first trimester precede intrauterine growth restriction associated with placental insufficiency

The aim of this study was to investigate whether maternal serum levels of angiopoietin-2 (Ang-2) and pregnancy-associated plasma protein A (PAPP-A) are associated with subsequent intrauterine growth restriction (IUGR). Ang-2 was measured in 29 nonpregnant and 44 pregnant women at 10–13 weeks of gestation. The median concentration of Ang-2 was 26.61 ng/ml in normal pregnant women compared with 1.71 ng/ml in nonpregnant controls ( P < 0.01). Women who subsequently developed severe IUGR had lower levels of Ang-2 compared with normal pregnant controls ( P < 0.01). PAPP-A levels were similar in all pregnant groups. These findings suggest that Ang-2 should be evaluated for its ability to predict pregnancies that later are affected by IUGR.     

Role of low placental share in twin-twin transfusion syndrome complicated by intrauterine growth restriction

Objectives

Prior studies have demonstrated that donor twin survival following treatment of twin-twin transfusion syndrome (TTTS) was highly associated with donor intrauterine growth restriction (IUGR). Here, we hypothesized that donor IUGR may be attributed in part to low placental share.

Study design

The study population consisted of all patients who underwent laser treatment for TTTS at a single institution between 2006-2010. Only those pregnancies with dual survival at birth were included so that placental share information could be interpreted. We examined the relationships between Quintero Stage (with separate analysis of Stage III patients with critically abnormal donor Doppler findings) and low placental share (defined as ≤ 30%) with IUGR (<10th percentile) using chi-square analysis and multivariable logistic regression modeling.

Results

Of 210 patients treated, 159 (75.7%) had dual survivors at birth. Of these, placental share was documented in 90 cases (56.6%). Twenty-seven (30.0%) had low placental share, and 37 (41.1%) had IUGR. IUGR was associated with low placental share (63.0% vs. 31.7%, P = 0.0116). IUGR was also associated with Stage III patients (57.4% vs. 23.3%, P = 0.0021), and in particular with Stage III patients with donor involvement (77.8% vs. 25.4%, P < 0.0001). In logistic regression modeling, both low placental share and Stage III with donor involvement were independent risk factors for IUGR (OR = 3.5 [1.2-10.3], P = 0.0206, and OR = 10.1 [3.3-30.6], P < 0.0001, respectively).

Conclusions

Donor IUGR in TTTS pregnancies appears to be associated, in part, with low placental share.     

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.     

The common prothrombotic factors in nulliparous women do not compromise blood flow in the feto-maternal circulation and are not associated with preeclampsia or intrauterine growth restriction

OBJECTIVE: In this study we evaluated the associations between common prothrombotic factors and increased blood flow resistance in the feto-maternal circulation, intrauterine growth restriction, small for gestational age, or preeclampsia. STUDY DESIGN: A prospective study was conducted in healthy nulliparous women with spontaneous singleton pregnancy. Blood was tested for the common prothrombotic factors, i.e., factor V Leiden, factor II G20210A, methylenetetrahydrofolate reductase C677T, anticardiolipin, and lupus anticoagulant. Blood flow resistance in the uterine, placental, and umbilical arteries were assessed by multigate Doppler and compared between women with and without prothrombotic factors. The maternal, fetal, and neonatal clinical courses were also compared among these subgroups. RESULTS: Prothrombotic factors were detected in 191 of 637 (30%) subjects. No significant difference in resistance to blood flow in the feto-maternal unit was discernible between women with and without prothrombotic factors. Pregnancy-induced hypertension or preeclampsia occurred in 10 of 191 (5.2%) and in 19 of 446 (4.3%) of women with and without a prothrombotic factor respectively ( P = .59). Intrauterine growth restriction was detected at 31 weeks in 13 of 164 (7.9%) and in 42 of 377 (11.1%) fetuses of women with and without a prothrombotic factor ( P = .26), and small for gestational age at delivery was observed in 19 of 187 (10.2%) and in 41 of 413 (9.9%) of mothers with and without prothrombotic markers, respectively. CONCLUSION: The presence of prothrombotic factors in healthy nulliparous women does not compromise blood flow in the feto-maternal unit, nor is it associated with preeclampsia, intrauterine growth restriction, or small for gestational age .     

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.     

Long-term maternal morbidity and mortality associated with ischemic placental disease

Ischemic placental disease can have long-term maternal health implications. In this article, we discuss the three conditions of ischemic placental disease (preeclampsia, fetal growth restriction, and abruption placenta) and its associated long-term maternal morbidity. Retrospective observational studies comparing pregnancies complicated by ischemic placental disease to uncomplicated pregnancies suggest an increased long-term risk of hypertension, cardiovascular death, metabolic syndrome, and cerebrovascular disease. This association is much stronger in women who had an indicated-preterm delivery due to ischemic placental disease. It is important to adequately counsel women who are diagnosed with these conditions about their future health risks. Increased awareness of the potential health risks and multidisciplinary collaboration remains paramount to instituting the appropriate screening and preventative strategies (i.e., behavior modification) for affected women.     

Placental pathologies associated with intra-uterine fetal growth restriction complicated with and without oligohydramnios

Purpose  To compare the placental pathologies and perinatal outcomes in fetal growth restriction (FGR) pregnancies with and without oligohydramnios. Methods  A retrospective cohort study, comparing placental findings in all singleton deliveries with FGR. Results  Macroscopic placental findings were available for 1,104 singleton FGR pregnancies. A total of 397 placentas were microscopically examined; of which 89 placentas were of FGR neonates who had oligohydramnios. No significant differences in placental vascular mal-perfusion were found between pregnancies with and without oligohydramnios (69.3 vs. 74.3%; P = 0.357). Likewise, no significant differences were noted between the groups regarding diffuse villous fibrosis (10.1 vs. 4.9%; P = 0.573), and amnion cell metaplasia (65.9 vs. 64.3%; P = 0.779). Cases of FGR complicated with oligohydramnios had significantly higher rates of perinatal mortality (9.9 vs. 5.9%; P = 0.028), preterm deliveries (34.9 ± 3.4 vs. 35.4 ± 3.1 weeks of pregnancy; P = 0.041), and lower birth weight (1,737 ± 542 vs. 1,845 ± 467 g; P = 0.002) compared to FGR without oligohydramnios. Conclusions  Oligohydramnios is a significant risk factor for adverse perinatal outcome in FGR pregnancies; nevertheless, no significant differences in placental pathologies were noted. Presented in part at the 29th Annual Meeting of the Society of Maternal Fetal Medicine (SMFM), San Diego, CA, USA, 26–31 January 2009.     

Placental pathologic changes of maternal vascular underperfusion in bronchopulmonary dysplasia and pulmonary hypertension

Introduction

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy, and BPD-associated pulmonary hypertension (PH) is a serious complication that can negatively impact later childhood health. There is growing evidence that lung injury leading to BPD and PH is due to chronic fetal hypoxia-ischemia. The purpose of this study was to investigate whether placental pathologic changes of maternal vascular underperfusion (MVU) are associated with BPD, and further increased with PH.

Methods

We conducted a 5-year retrospective cohort study of premature infants born ≤28 weeks. BPD was defined as persistent oxygen requirement at 36 weeks corrected gestational age. PH was identified using a standardized algorithm of echocardiogram review. Archived placental slides underwent standardized masked histopathologic review. Logistic regression modeling was performed, taking into account important maternal and infant covariates.

Results

Among 283 births, 121 had MVU, of which 67 (55%) developed BPD, and 24 (20%) had PH. Among the common neonatal complications of extreme prematurity, BPD was the only outcome that was increased with MVU (P < 0.001). After adjustment for birth weight, fetal growth restriction, preeclampsia and other factors, infants with MVU were more likely to develop BPD (adjusted odds ratio = 2.6; 95% confidence interval = 1.4, 4.8). Certain MVU sublesions (fibrinoid necrosis/acute atherosis and distal villous hypoplasia/small terminal villi) were increased with PH (P < 0.001).

Discussion

Placental MVU may identify BPD infants who were exposed to intrauterine hypoxia-ischemia, which increases their risk for development of PH disease.

Conclusions

Our findings have important implications for providing earlier and more effective therapies for BPD.     

Detection of maternal uniparental disomy 9 in association with low-level mosaic trisomy 9 at amniocentesis in a pregnancy associated with intrauterine growth restriction,abnormal first-trimester screening result (low PAPP-A and low PlGF), maternal preeclampsia and a favorable outcome

ObjectiveWe present detection of maternal uniparental disomy (UPD) 9 in association with low-level mosaic trisomy 9 at amniocentesis in a pregnancy associated with intrauterine growth restriction (IUGR), an abnormal first-trimester maternal serum screening result, abnormal non-invasive prenatal testing (NIPT), maternal preeclampsia and a favorable outcome.Case reportA 37-year-old, primigravid woman underwent first-trimester maternal serum screening and NIPT at 11 weeks of gestation, which revealed a gene dosage increase in chromosome 9 and low levels of plasma protein-A (PAPP-A) and placental growth factor (PlGF) in maternal blood. The woman underwent amniocentesis at 16 weeks of gestation, which revealed a karyotype of 47,XX,+9[4]/46,XX[35] in cultured amniocytes. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed a result of arr [GRCh37] (9) × 3 [0.14] (X) × 2, compatible with mosaic trisomy 9. The parental karyotypes were normal. Repeat amniocentesis was performed at 20 weeks of gestation. The cultured amniocytes had a karyotype of 47,XX,+9[1]/46,XX[23]. The uncultured amniocytes had a mosaic trisomy 9 level of 10.7% (12/112 cells) by interphase fluorescence in situ hybridization (FISH), a mosaic trisomy 9 level of 10–14% (log₂ ratio = 0.1) by aCGH, and maternal uniparental isodisomy 9 by polymorphic DNA marker analysis. Prenatal ultrasound revealed IUGR, and the mother had preeclampsia. At 29 weeks of gestation, a 1054-g phenotypically normal baby was delivered because of preterm labor. The cord blood and umbilical cord had the karyotype of 46, XX and maternal UPD 9 and isodisomy 9, while the placenta had trisomy 9 of maternal origin. Postnatal FISH anlaysis on 101 buccal mucosal cells and 100 urinary cells at age three months detected no trisomy 9 signals. The baby was doing well at age six months.ConclusionPregnancy with low-level mosaic trisomy 9 and maternal UPD 9 at amniocentesis can be associated with IUGR, maternal preeclampsia and a favorable outcome. Fetuses with maternal UPD 9 can be associated with an abnormal NIPT result concerning chromosome 9, an abnormal first-trimester maternal serum screening result (low PAPP-A and low PlGF) and mosaic trisomy 9 at amniocentesis.     

Inflammation-induced fetal growth restriction in rats is associated with altered placental morphometrics

Introduction

Evidence links alterations in placental shape and size to fetal growth restriction (FGR). Here we determined whether alterations in placental morphometrics are linked to FGR induced by abnormal maternal inflammation.

Methods

We used an inflammation-induced model of FGR in which pregnant rats receive lipopolysaccharide (LPS) on gestational days (GD) 13.5–16.5. Fetal weights were matched to various parameters of placental morphometrics including weight, area, minor and major axes lengths and thickness.

Results

Compared with saline administration, LPS administration was associated with altered placental morphometrics, including reduced placental weight, decreased placental area and a trend towards reduced placental thickness. When data were dichotomized as FGR or normal-sized fetuses within treatment groups, a significant increase in the placental-weight-to-fetal-weight ratio and placental thickness was observed only in the saline-associated FGR subgroup. Multivariable linear regression revealed that the lengths of the major and minor placental axes were predictors of fetal weight, regardless of treatment modality. Subgroup regression analysis by treatment revealed that the lengths of the major and minor placental axes were predictors of fetal weight in the saline-treatment group while only the minor placental axis was a predictor of fetal weight in the LPS cohort. Finally, placental area and the length of the minor placental axis were correlated with implantation site location only in the saline-treatment group.

Discussion/conclusion

These findings indicate that inflammation-induced FGR is associated with alterations in placental morphometrics. Our data reveal that the mechanisms leading to inflammation-induced FGR may be different from the mechanisms leading to idiopathic FGR.     

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.