Maternal serum biomarkers of placental insufficiency at 24-28 weeks of pregnancy in relation to the risk of delivering small-for-gestational-age infant in Sylhet, Bangladesh: a prospective cohort study.

BACKGROUND: Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA. METHODS: Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders. RESULTS: The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025). CONCLUSIONS: This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.

Diagnosis of placental insufficiency independently of clinical presentations using sFlt-1/PLGF ratio, including SGA patients.

INTRODUCTION: Angiogenic markers (sFLt1 and PlGF) are altered in preeclampsia and related placental insufficiency syndromes. The utility of these markers in various types of placental insufficiency is still not well known. AIMS: We analyzed blood specimens from 918 women with suspected or confirmed preeclampsia, HELLP syndrome, abruptio placenta, SGA, gestational hypertension for angiogenic markers - sFLT1, PlGF, sFlT1/PlGF ratios and studied them at various gestational windows. RESULTS: sFlt-1/PLGF ratio shows high sensitivity and specificity in all placental insufficiency cases independent of clinical forms below 34 weeks (AUC 0.964 respectively 0.834 34-37 weeks' and 0.843 >37 weeks). In preeclampsia or HELLP, they maintain a high specificity and sensitivity also after 34 weeks of gestation. SGA prior to 34 weeks' gestation displayed severe placental angiogenesis disorders, with their share amounting to 78%. After 34 weeks, this share dropped to only slightly above 50%, and after the 37th week, a mere 38%. CONCLUSIONS: Placental angiogenesis markers may be useful in diagnosing many forms of placental ischemia syndromes, particularly when the disease presents early in gestation. In late-onset SGA cases, assessment of the diagnostic value of angiogenesis markers requires further analysis.

Maternal circulating SPINT1 is reduced in small-for-gestational age pregnancies at 26 weeks: Growing up in Singapore towards health outcomes (GUSTO) cohort study.

Fetal growth restriction arising from placental insufficiency is a leading cause of stillbirth. We recently identified low maternal circulating SPINT1 concentrations as a novel biomarker of poor fetal growth. Here we measured SPINT1 in a prospective cohort in Singapore. Circulating SPINT1 concentrations were significantly lower among 141 pregnant women destined to deliver small-for-gestational age infants (birthweight <10th centile), compared to 772 controls (p < 0.01) at as early as 26 weeks' gestation. There were no correlations between infant body composition and circulating SPINT1 concentrations at 26 weeks. This provides validation that low maternal SPINT1 concentration is associated with poor fetal growth.

Maternal and foetal placental vascular malperfusion in pregnancies with anti-phospholipid antibodies.

OBJECTIVE: The objective of the study was to evaluate the rates of pathological placental lesions among pregnant subjects positive for aPL antibodies. METHODS: We performed a longitudinal case-control study including 27 subjects with primary APS, 51 with non-criteria APS, 24 with aPL antibodies associated with other well-known CTDs enrolled at the end of the first trimester of pregnancy and 107 healthy controls. RESULTS: Compared with controls and after correction for multiple comparisons, primary, non-criteria APS and aPL associated to CTD, subjects had lower placental weight, volume and area. After penalized logistic regression analysis to correct for potential confounders, placental lesions suggesting severe maternal vascular malperfusion (MVM) were more common among primary [odds ratio (OR) 11.7 (95% CI 1.3, 108)] and non-criteria APS [OR 8.5 (95% CI 1.6, 45.9)] compared with controls. The risk of foetal vascular malperfusion (FVM) was higher in primary APS [OR 4.5 (95% CI 1.2, 16.4)], aPL associated with CTDs [OR 3.1 (95% CI 1.5, 6.7)] and non-criteria APS [OR 5.9 (95% CI 1.7, 20.1)] compared with controls. Among clinical and laboratory criteria of APS, first trimester aCL IgG >40 UI/ml [OR 4.4 (95% CI 1.3, 14.4)], LA positivity [OR 6.5 (95% CI 1.3, 33.3)] and a history of pre-eclampsia at <34 weeks [OR 32.4 (95% CI 6.5, 161)] were the best independent first trimester predictors of severe MVM [area under the curve 0.74 (95% CI 0.6, 0.87)]. CONCLUSION: Compared with healthy controls, pregnant subjects with aPL antibodies have an increased risk of placental lesions, suggesting MVM and FVM. First-trimester variables such as aCL IgG >40 UI/ml and a history of pre-eclampsia were significant predictors of both severe MVM and FVM.

Gestational vitamin D deficiency causes placental insufficiency and fetal intrauterine growth restriction partially through inducing placental inflammation.

Several epidemiological studies suggest an association between vitamin D deficiency (VDD) and fetal intrauterine growth restriction (IUGR). Here, we explored the mechanism through which VDD induced fetal IUGR. Pregnant mice were fed with VDD diet to establish VDD model. Cyp27b1+/- mice were generated to develop a model of active vitamin D3 deficiency. Cyp27b1+/- mice were injected with either 1α,25(OH)2D3 or vehicle once a day throughout pregnancy. As expected, fetal weight and crown-rump length were reduced in VDD diet-fed mice. Correspondingly, fetal weight and crown-rump length were lower in cyp27b1+/- mice. 1α,25(OH)2D3 elevated fetal weight and crown-rump length, and protected cyp27b1+/- mice from fetal IUGR. Further analysis found that placental proliferation was inhibited and placental weight was decreased in VDD diet-fed mice. Several growth factors and nutrient transfer pumps were downregulated in the placentas of VDD diet-fed mice. Mechanistically, several inflammatory cytokines were upregulated and placental NF-κB was activated not only in VDD diet-fed mice but also in VDD pregnant women. Interestingly, 1α,25(OH)2D3 inhibited the downregulated of placental nutrient transfer pumps and the upregulated of placental inflammatory cytokines in Cyp27b1+/- mice. These results provide experimental evidence that gestational VDD causes placental insufficiency and fetal IUGR may be through inducing placental inflammation.

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.

BACKGROUND: Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. METHODS: We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. RESULTS: In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. CONCLUSIONS: Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

Maternal plasma proteomics in a rat model of pregnancy complications reveals immune and pro-coagulant gene pathway activation.

PROBLEM: The Brown Norway (BN) rat is a model of T-helper 2 immune diseases, and also a model of pregnancy disorders that include placental insufficiency, fetal loss, and pre-eclampsia-like symptoms. The aim of this study was to investigate the plasma proteomic/cytokine profile of pregnant BN rats in comparison to that of the Lewis (LEW) rat strain. METHOD OF STUDY: Plasma proteomics differences were studied at day 13 of pregnancy in pooled plasma samples by differential in-gel electrophoresis, and protein identification was performed by mass spectrometry. Key protein findings and predicted cytokine differences were validated by ELISA using plasma from rats at various pregnancy stages. Proteomics data were used for ingenuity pathway analysis (IPA). RESULTS: In-gel analysis revealed 74 proteins with differential expression between BN and LEW pregnant dams. ELISA studies confirmed increased maternal plasma levels of complement 4, prothrombin, and C-reactive protein in BN compared to LEW pregnancies. LEW pregnancies showed higher maternal plasma levels of transthyretin and haptoglobin than BN pregnancies. Ingenuity pathway analysis revealed that BN pregnancies are characterized by activation of pro-coagulant, reactive oxygen species, and immune-mediated chronic inflammation pathways, and suggested increased interleukin 6 and decreased transforming growth factor-ß1 as potential upstream events. Plasma cytokine analysis revealed that pregnant BN dams have a switch from anti- to pro-inflammatory cytokines with the opposite switch observed in pregnant LEW dams. CONCLUSION: Brown Norway rats show a maternal pro-inflammatory response to pregnancy that likely contributes to the reproductive outcomes observed in this rat strain.

What's new in obstetric antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a rare systemic autoimmune disease, the obstetric features of which include recurrent early miscarriage, fetal death at or beyond 10 weeks of gestation, and early delivery for severe preeclampsia or placental insufficiency. Controversies regarding the specificity of these obstetric clinical features, as well as the laboratory diagnostic criteria, are the subject of current debate and reanalysis. Clinical and laboratory features can be used to stratify women with APS in terms of risk of adverse second and third trimester pregnancy outcomes. Numerous "treatments" have been used in high-risk and refractory patients, but rigorously designed clinical trials are needed. APS is a rare disease that requires innovative investigative approaches to provide credible results.

The sFlt-1/PlGF ratio values within the <38, 38-85 and >85 brackets as compared to perinatal outcomes.

Background Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are used as markers of preeclampsia. The aim of this paper was to assess the correlations between the sFlt-1/PlGF ratio values within the <38, 38-85 and >85 brackets and perinatal outcomes in pregnancies that require determination of these markers. Methods A total of 927 pregnant patients between 18 and 41 weeks' gestation suspected of or confirmed with any form of placental insufficiency (preeclampsia, intrauterine growth restriction [IUGR], gestational hypertension, HELLP syndrome, placental abruption) were included in the study. In each of the patients, the sFlt-1/PlGF ratio was calculated. Patients were divided into three groups according to the sFlt-1/PlGF ratio brackets of <38, 38-85 and >85. Results Significantly worse perinatal outcomes were found in the sFlt-1/PlGF >85 group, primarily with lower cord blood pH, neonatal birth weight and shorter duration of gestation. Statistically significant correlations between the values of these markers and the abovementioned perinatal effects were found. Conclusion An sFlt-1/PlGF ratio value of >85 suggests that either preeclampsia or one of the other placental insufficiency forms may occur, which is associated with lower cord blood pH, newborn weight and earlier delivery. Determining the disordered angiogenesis markers and calculating the sFlt-1/PlGF ratio in pregnancies complicated by placental insufficiency may lead to better diagnosis, therapeutic decisions and better perinatal outcomes.

Early-Pregnancy Circulating Antioxidant Capacity and Hemodynamic Adaptation in Recurrent Placental Syndrome: An Exploratory Study.

BACKGROUND/AIMS: Placental syndromes (PS) refer to pregnancy complications that include gestational hypertension, (pre)eclampsia, HELLP syndrome, and/or placental insufficiency-induced fetal growth restriction. These disorders are characterized by increased oxidative stress. This study aims to test the hypothesis that the abnormal hemodynamic adaptation to pregnancy, typical for early PS pregnancy, is accompanied by abnormal maternal levels of antioxidants relative to those in normal pregnancy. METHODS: Before, and at 12, 16, and 20 weeks pregnancy, we measured trolox equivalent antioxidant capacity (TEAC), uric acid (UA), and TEACC (TEAC corrected for UA) in maternal serum of former PS patients, who either developed recurrent PS (rPS; n = 16) or had a normal next pregnancy (non-rPS; n = 23). Concomitantly, we also measured various hemodynamic variables. RESULTS: rPS differed from non-rPS by higher TEACC levels before pregnancy (178 vs. 152 µM; p = 0.02) and at 20 weeks pregnancy (180 vs. 160 µM; p = 0.04). Only non-rPS responded to pregnancy by significant rises in hemodynamic measures. CONCLUSION: These data indicate that rPS pregnancies are preceded by an increase in antioxidant capacity, presumably induced by subclinical vascular injury and low-grade chronic inflammation.

Does an abnormally elevated maternal alkaline phosphatase pose problems for the fetus?

We report a potential association between an abnormally raised pregnancy level of alkaline phosphatase (ALP) and intrauterine growth restriction (IUGR). There are few reports of women with abnormally high ALP during pregnancy. However, there is work to suggest an association with placental insufficiency, low birth weight and preterm delivery. In conjunction with a rising ALP, fetal IUGR and intermittent absence of umbilical artery end diastolic flow had evolved. A greatly elevated ALP may be a marker for placental insufficiency and IUGR.

Chronically Hypoxic Fetal Lambs Supported by an Extra-Uterine Device Exhibit Mitochondrial Dysfunction and Elevations of Hypoxia Inducible Factor 1-Alpha.

INTRODUCTION: We have recently developed an extra-uterine environment for neonatal development (EXTEND) capable of supporting premature fetal lambs and have been able to replicate hypoxic in utero conditions by controlling fetal oxygen delivery. In this study, we investigated the fetal mitochondrial response to hypoxia. METHODS: Eight premature fetal lambs were delivered via hysterotomy and transitioned to extra-uterine support for 3 weeks. The lambs were divided into 2 groups: normoxic fetuses which maintained physiologic oxygen delivery and hypoxic fetuses in which oxygen delivery was significantly reduced. Control fetuses were delivered via hysterotomy but not cannulated. Measurements of mitochondrial membrane potential (MMP) were performed in peripheral blood mononuclear cells. RESULTS: There were no significant differences in MMP between normoxic EXTEND fetuses and controls. Hypoxic fetuses had significantly more depolarized mitochondria compared to normoxic fetuses overall, and these changes were specifically appreciated in weeks 1 and 2, but not by week 3. Hypoxic fetuses had significantly elevated levels of HIF-1α compared to normoxic fetuses in the first 2 weeks. DISCUSSION: Normoxic fetal lambs supported by EXTEND demonstrate normal mitochondrial function as evidenced by equivalent membrane potentials compared to control fetuses. Hypoxic fetuses exhibit mitochondrial dysfunction, though they do show evidence of adaptation after 3 weeks of hypoxic exposure.

IUGR impairs cardiomyocyte growth and maturation in fetal sheep.

Placental insufficiency causes intrauterine growth restriction (IUGR), a common complication of pregnancy. In skeletal muscle, IUGR reduces fetal myofibril size, reduces myoblast proliferation and reduces expression of genes in cell cycle regulation clusters. The myocardium is striated like skeletal muscle, and IUGR also reduces cell cycle activity and maturation in cardiomyocytes, despite cardiac output preferentially directed to the coronary circulation. We hypothesized that cardiomyocyte growth restriction would be accompanied by similar changes in cell cycle regulation genes and would reduce cardiomyocyte cell cycle activity, number, maturity and size. Pregnant ewes were housed in elevated ambient temperatures from ~40 to ~115 days of gestation (dGA) to produce placental insufficiency and IUGR; fetal hearts were studied at ~134 dGA. Hearts were biopsied for mRNA analysis and then dissociated into individual myocytes (Control n = 8; IUGR n = 15) or dissected (Control n = 9; IUGR n = 13). IUGR fetuses had low circulating insulin and insulin-like growth factor 1 (IGF1) and high circulating cortisol. Bodies and hearts of IUGR fetuses were lighter than those of Controls. Cardiomyocytes of IUGR fetuses were smaller, less mature, less active in the cell cycle and less numerous than in Controls. Further, there was a pattern of downregulation of cell cycle genes in IUGR ventricles. IUGR growth profiles in heart and skeletal muscle suggest similar regulation despite differences in blood and nutrient delivery prioritization. IGF1 signaling is suggested as a mechanism regulating altered growth in IUGR striated muscle and a potential therapeutic candidate.

Antiphospholipid antibodies in women with severe preeclampsia and placental insufficiency: a case-control study.

Objective Preterm delivery for preeclampsia or placental insufficiency (PREPI) is a clinical criterion for antiphospholipid syndrome (APS), but no prior prospective studies have used the international classification criteria for APS. Our objective is to determine the proportion of women with PREPI who test positive for aPL using international criteria for antiphospholipid antibody (aPL) assays. Methods We conducted a prospective, case-control study of 148 women delivered < 36 weeks because of PREPI compared to 148 controls. PREPI cases delivered < 36 weeks were compared to matched controls. Cases and controls were tested for aPL. Demographic variables were compared with chi-squared and Wilcoxon-rank-sum statistics. Rates of + aPL were compared using adjusted odds ratios (aORs) for maternal body mass index (BMI) and Caucasian race. Positive aPL (+aPL) was defined as lupus anticoagulant (LA), anticardiolipin (aCL) immunoglobulin G (IgG) (GPL) or immunoglobulin M (IgM) (MPL) ≥ 40, or anti-ß2-glycoprotein I (aß2GPI) IgG (SGU) or IgM (SMU) ≥ 40. Results Controls were more likely to be Caucasian (87% vs 70%, p = 0.006) and had lower BMIs (BMI 26 vs 33, p < 0.001). Positive aPL were found more commonly in cases than controls (11.5% vs 1.4%, aOR 8.9 (95% CI 1.9-41.4)). In + aPL cases, 76% had + LA, 41% had + aCL, and 24% had + aß2GPI. Conclusion Women requiring early delivery for PREPI are more likely to have aPL (and thus APS) than controls. This is the first prospective study using both obstetric definitions and laboratory criteria in accordance with APS international criteria.

Study of mitochondrial function in placental insufficiency.

INTRODUCTION: It has been suggested that mitochondria play a crucial role in sustaining pregnancy and foetal growth. The aim of the study was to assess the influence of mitochondrial functions and genetics on placental insufficiency diseases. METHODS: A total of 115 patients were recruited, subdivided into 74 placenta samples and 41 maternal blood samples: placental insufficiency diseases including intra uterine growth restriction (IUGR) (n = 35), preeclampsia (PE) (n = 13), IUGR associated to PE (PER) (n = 25); and controls (n = 42). Haplogroups were determined for all patients. Eighty-six placenta samples were studied for quantitative and qualitative analyses of mtDNA: IUGR (n = 25), PE (n = 1), PER (n = 18) and controls (n = 42). Sixteen placenta samples were selected for functional analysis: IUGR (n = 6), PER (n = 2) and controls (n = 8). RESULTS: Mitochondrial DNA copy numbers and rearrangements and haplogroup distribution were not significantly altered in the patient group. Enzyme activity and expression of respiratory chain complexes were also comparable between both groups. DISCUSSION: Our results do not argue in favour of a mitochondrial involvement in placental insufficiency, suggesting that the glycolytic pathway may represent a key energetic source in placental insufficiency diseases.

Utility of metabolic profiling of serum in the diagnosis of pregnancy complications.

INTRODUCTION: Currently there are no clinical screening tests available to identify pregnancies at risk of developing preeclampsia (PET) and/or intrauterine growth restriction (IUGR), both of which are associated with abnormal placentation. Metabolic profiling is now a stable analytical platform used in many laboratories and has successfully been used to identify biomarkers associated with various pathological states. METHODS: We used nuclear magnetic resonance spectroscopy (NMR) to metabolically profile serum samples collected from 143 pregnant women at 26-41 weeks gestation with pregnancy outcomes of PET, IUGR, PET IUGR or small for gestational age (SGA) that were age-matched to normal pre/term pregnancies. RESULTS: Spectral analysis found no difference in the measured metabolites from normal term, pre-term and SGA samples, and of 25 identified metabolites, only glutamate was marginally different between groups. Of the identified metabolites, 3-methylhistidine, creatinine, acetyl groups and acetate, were determined to be independent predictors of PET and produced area under the curves (AUC) = 0.938 and 0.936 for the discovery and validation sets. Only 3-hydroxybutyrate was determined to be an independent predictor of IUGR, however the model had low predictive power (AUC = 0.623 and 0.581 for the discovery and validation sets). CONCLUSIONS: A sub-panel of metabolites had strong predictive power for identifying PET samples in a validation dataset, however prediction of IUGR was more difficult using the identified metabolites. NMR based metabolomics can identify metabolites strongly associated with disease and has the potential to be useful in developing early clinical screening tests for at risk pregnancies.

Screening for fetal growth restriction and placental insufficiency.

Fetal growth restriction (FGR) continues to be a leading cause of preventable stillbirth and poor neurodevelopmental outcomes in offspring, and furthermore is strongly associated with the obstetrical complications of iatrogenic preterm birth and pre-eclampsia. The terms small for gestational age (SGA) and FGR have, for too long, been considered equivalent and therefore used interchangeably. However, the delivery of improved clinical outcomes requires that clinicians effectively distinguish fetuses that are pathologically growth-restricted from those that are constitutively small. A greater understanding of the multifactorial pathogenesis of both early- and late-onset FGR, especially the role of underlying placental pathologies, may offer insight into targeted treatment strategies that preserve placental function. The new maternal blood biomarker placenta growth factor offers much potential in this context. This review highlights new approaches to effective screening for FGR based on a comprehensive review of: etiology, diagnosis, antenatal surveillance and management. Recent advances in novel imaging methods provide the basis for stepwise multi-parametric testing that may deliver cost-effective screening within existing antenatal care systems.

A placenta clinic approach to the diagnosis and management of fetal growth restriction.

Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction.

The Role of Interleukin-17, Interleukin-23, and Transforming Growth Factor-ß in Pregnancy Complicated by Placental Insufficiency.

AIM: The aim of the study was to evaluate the role of Interleukin-17 (IL-17), Interleukin-23 (IL-23), and transforming growth factor-ß (TGF-ß) in pregnancy complicated by placental insufficiency and in normal pregnancy. MATERIAL AND METHODS: The study comprised 34 patients with pregnancy complicated by fetal growth restriction (FGR) associated with preeclampsia (PE), as well as 35 healthy pregnant women. The concentrations of IL-17, IL-23, and TGF-ß in sera from maternal peripheral blood were determined by an immunoenzymatic assay. RESULTS: There were higher concentrations of IL-17 in the study group when compared to the controls. In the group of patients with placental insufficiency, the levels of IL-17 positively correlated with systolic blood pressure (R = 0.42, p < 0.01). The study obtained comparable concentrations of IL-23 in both studied groups. The concentrations of TGF-ß were significantly lower in pregnancy complicated by the insufficiency of placenta when compared to the controls. CONCLUSIONS: It seems possible that the increased concentrations of IL-17 and the deficiency of TGF-ß in pregnancy complicated by FGR and PE can be responsible for the activation of inflammatory response observed in PE cases.

MR Imaging Measurements of Altered Placental Oxygenation in Pregnancies Complicated by Fetal Growth Restriction.

Purpose To evaluate oxygen-enhanced and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging parameters in normal pregnancies and those complicated by fetal growth restriction (FGR). Materials and Methods This case-control study was approved by the local research ethics committee. Informed consent was obtained from all subjects. From October 2010 to October 2015, 28 women with uncomplicated pregnancies (individualized birthweight ratio [IBR] >20th percentile and delivery >37 weeks) and 23 with pregnancies complicated by FGR (IBR <5th percentile and abnormal Doppler ultrasonography [US] studies) underwent MR imaging. Differences in placental longitudinal R1 (1/T1) and transverse R2* (1/T2*) were quantified, with subjects breathing either air or oxygen. The difference in R1 (ΔR1) after hyperoxia was converted to change in partial pressure of oxygen (ΔPo2). Data were acquired prospectively, with retrospective interpretation of group differences (unpaired t tests). Diagnostic models were developed by using logistic regression analysis with gestational age as a covariate. Results The mean baseline R1 and R2* for normal pregnancies (R1: 0.59 sec-1, 95% confidence interval [CI]: 0.58 sec-1, 0.60 sec-1; R2*: 17 sec-1, 95% CI: 14 sec-1, 20 sec-1) were significantly different from those of pregnancies complicated by FGR (R1: 0.63 sec-1, 95% CI: 0.62 sec-1, 0.65 sec-1; R2*: 26 sec-1, 95% CI: 22 sec-1, 32 sec-1) (P < .0001). The ΔR1 showed a significant negative association with gestational age (P < .0001) in the combined cohort, with the FGR group having a ΔR1 that was generally 61.5% lower than that in the normal pregnancy group (P = .003). The area under the receiver operating characteristic curve for the differentiation between pregnancy complicated by FGR and normal pregnancy by using ΔPo2, baseline R1, and baseline R2* was 0.91 (95% CI: 0.82, 0.99). Conclusion R1, R2*, and ΔPo2 were significantly different between normal pregnancies and those complicated by severe FGR. MR imaging parameters have the potential to help identify placental dysfunction associated with FGR and may have clinical utility in correctly identifying FGR among fetuses that are small for gestational age. A larger prospective study is needed to assess the incremental benefit beyond that offered by US. © RSNA, 2017.