Placental Biomarkers Research Articles

Alteration in sB7-H4 Serum Levels and Placental Biomarker Expression after Therapeutic Plasma Exchange in Early-Onset Preeclampsia Patients

Therapeutic plasma exchange (TPE) is a widely used treatment for numerous diseases including pregnancy-related conditions. Our prior study on 20 early-onset preeclampsia patients undergoing TPE revealed a significant extension in pregnancy duration and reduced serum levels of sFlt-1, sFlt-1/PlGF, and sEndoglin. Here, we investigated the impact of TPE on serum sB7-H4, an immunological checkpoint molecule, and placental proteins (Flt-1, Eng, B7-H4, iNOS, TNF-α) in TPE-treated early-onset preeclampsia patients (N = 12, 23 + 2–28 + 5 weeks), conventionally treated counterparts (N = 12, 23 + 5–30 weeks), and gestational age-matched controls (N = 8, 22 + 4–31 + 6 weeks). Immunoblotting, ELISA, and co-immunohistochemistry were used for biomarker analysis, including placental inflammation factors (iNOS, TNF-α). The results showed that TPE extended pregnancy by a median of 6.5 days in this cohort of early-onset preeclampsia. Serum sB7-H4, sFlt-1, and sEndoglin levels decreased, along with reduced expression of their membrane-bound proteins in placental tissue upon TPE treatment. Moreover, TPE-treated patients displayed reduced placental inflammation compared to preeclampsia patients receiving standard-of-care treatment. In conclusion, TPE may improve pregnancy outcomes in early-onset preeclampsia by lowering circulating levels of sB7-H4, sFlt-1, and sEndoglin, as well as reducing placental inflammation. This translational approach holds promise for enhancing placental function and extending gestation in high-risk pregnancies including very preterm PE or HELLP cases.

Maternal Thyroid Function and Biochemical Markers of Placental Function in Early Pregnancy.

A link between maternal thyroid function and the placental biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), has been brought forward. This study aimed to describe their association in early pregnancy. Retrospective cohort study. Eight hundred and fifty-eight pregnant women from the North Denmark Region, 2013, with blood samples drawn in early pregnancy. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), thyroid-peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab) (ADVIA Centaur XPT, Siemens Healthineers), sFlt-1 and PlGF (Kryptor Compact, ThermoFisher Scientific) were measured. The association between maternal TSH and fT4 and percentile (pc) levels of sFlt-1 and PlGF (< 25th pc, 25-75th pc, > 75th pc) was evaluated using regression analysis and reported as adjusted beta coefficient (aβ). The frequency of maternal thyroid autoantibodies (TPO-Ab > 60 U/mL or Tg-Ab > 33 U/mL) by pc levels of sFlt-1 and PlGF was compared using chi-squared test. Higher levels (> 75th pc) of sFlt-1 associated with lower TSH (aβ 0.62, 95% CI: 0.51-0.76) and higher fT4 (aβ 1.03, 95% CI: 1.01-1.05). Higher levels of PlGF associated with lower TSH (aβ 0.82, 95% CI: 0.69-0.98), but not with levels of fT4 (aβ 1.00, 95% CI: 0.97-1.02). No association with maternal thyroid autoantibodies was found (TPO-Ab: sFlt-1: p-value 0.5 and PlGF: p-value 0.1; Tg-Ab: sFlt-1: p-value 0.7 and PlGF: p-value 0.1). In a large cohort of Danish pregnant women, higher levels of sFlt-1 and PlGF associated with maternal thyroid function in early pregnancy, while there was no association with maternal thyroid autoantibodies.

Utility of placental biomarkers and fetoplacental Dopplers in predicting likely placental pathology in early and late fetal growth restriction – A prospective study

IntroductionThe aim of this study was to evaluate the association between placental abnormalities, placental biomarkers, and fetoplacental Dopplers in a cohort of pregnancies complicated by fetal growth restriction (FGR). We also ascertained the risk of perinatal mortality, severe neurological morbidity, and severe non-neurological morbidity by type of placental abnormality. MethodsThis was a prospective cohort study. Multivariable logistic regression was used to evaluate the effect of early vs. late FGR, placental biomarkers and fetoplacental Dopplers on Maternal Vascular Malperfusion (MVM) which was the commonest placental abnormality identified. ResultsThere were 161 (53.5 %) early FGR and 140 (46.5 %) late FGR cases. MVM abnormalities were present in 154 (51.2 %), VUE in 45 (14.6 %), FVM in 16 (5.3 %), DVM in 14 (4.7 %) and CHI in 4 (1.3 %) cases. The odds of MVM were higher in early compared to late FGR cohort (OR 1.89, 95%CI 1.14, 3.14, p = 0.01). Low maternal PlGF levels <100 ng/L (OR 2.34, 95%CI 1.27,4.31, p = 0.01), high sFlt-1 level (OR 2.13, 95%CI 1.35, 3.36, p = 0.001) or elevated sFlt-1/PlGF ratio (OR 3.48, 95%CI 1.36, 8.91, p = 0.01) were all associated with MVM. Increased UA PI > 95th centile (OR 2.91, 95%CI 1.71, 4.95, p=<0.001) and mean UtA PI z-score (OR 1.74, 95%CI 1.15, 2.64, p = 0.01) were associated with higher odds of MVM. Rates of severe non-neurological morbidity were highest in the MVM, FVM, and CHI cohorts (44.8 %, 50 %, and 50 % respectively). ConclusionMVM was the commonest placental abnormality in FGR, particularly in early-onset disease. Low maternal PlGF levels, high sFlt-1 levels, elevated sFlt-1/PlGF ratio, and abnormal fetoplacental Dopplers were also significantly associated with MVM. MVM, FVM, and CHI abnormalities were associated with lower median birthweight, higher rates of preterm birth, operative birth for non-reassuring fetal status, and severe neonatal non-neurological morbidity.

Maternal Placental Growth Factor (PlGF) levels, sonographic placental parameters, and outcomes of IVF pregnancies with and without embryo trophectoderm biopsy.

In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF).Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy. This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups. The median PlGF level was 614.5 pg/mL (IQR 406-1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552-1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, -410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes. This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.

Placental biophysical model for prediction of early onset fetal growth restriction in first and second trimester of pregnancy: A prospective cohort study

IntroductionTo assess the placental biometry, placental biomarkers and uterine artery Doppler in each trimester of pregnancy for prediction of early-onset fetal growth restriction (EO FGR). MethodsIn this prospective cohort study placental biometry; biomarkers PAPP-A, sFLT-1, and PlGF along with the uterine artery blood flow evaluation was done serially at 11–14, 20–24 and 28–32 weeks of gestation. The above parameters were compared between women with early onset FGR and controls. ResultsOut of 1008 fully followed cases, the small for gestational age fetuses were 227/1008 (22.5 %), and EO FGR were 84/1008(8.3 %).The placental length, volume, and PlGF levels were significantly lower, whereas the uterine artery PI(Ut PI) was significantly higher at all time points among cases. The sFLT-1 level showed a significant increase among cases, whereas it decreased among controls from the first to the second trimester. The detection rate using PV/UtA PI was 60 % in the first trimester and 66.7 % in the second trimester at 30 % FPR. ConclusionThe PV/Ut PI in first and the second trimester was a good marker for the prediction of pregnancies at increased risk of developing EO FGR.

Placental biomarkers in the first trimester and adverse pregnancy outcome

Placental biomarkers in the first trimester and adverse pregnancy outcome

Dilatative fetal cardiomyopathy followed by amirror syndrome.

Mirror syndrome (Ballantyne syndrome) is arare condition characterized by maternal edema, which often affects the lungs. It mirrors the image of fetal and placental edema; therefore, it is also called triple edema. We present the case of a37-year-old secundigravida, referred to our clinic at 26weeks of apregnancy complicated by fetal dilatative restrictive cardiomyopathy and hydrops, placentomegaly, new-onset dyspnea, and maternal calf edema. Due to worsening mirror syndrome, preterm labor was induced. Labor was complicated, with soft tissue dystocia, stillbirth, and postpartum hemorrhage. The first pregnancy was also complicated by fetal right ventricular noncompaction dilatative cardiomyopathy. Aeutrophic male child was born vaginally at term and died due to deterioration of the cardiac disease in the third year of life. Next-generation sequencing panel for pediatric cardiology was performed in the deceased child and parents. Two gene variants were recorded: MYOM1: c.770_771delCA (p.Thr257fs) and TPM1: c.814G>A (p.Glu272Lys). Both variants were classified as variants of uncertain significance. This case emphasizes the importance of antenatal counseling, the timing of labor induction, appropriate management of possible complications such as postpartum hemorrhage and soft tissue dystocia, and the interpretation of placental biomarkers in the context of mirror syndrome. Finally, it contributes to understanding the clinical significance of the MYOM1 and TPM1 gene variants.

First Trimester Placental Biomarkers for Pregnancy Outcomes.

The placenta plays a key role in several adverse obstetrical outcomes, such as preeclampsia, intrauterine growth restriction and gestational diabetes mellitus. The early identification of at-risk pregnancies could significantly improve the management, therapy and prognosis of these pregnancies, especially if these at-risk pregnancies are identified in the first trimester. The aim of this review was to summarize the possible biomarkers that can be used to diagnose early placental dysfunction and, consequently, at-risk pregnancies. We divided the biomarkers into proteins and non-proteins. Among the protein biomarkers, some are already used in clinical practice, such as the sFLT1/PLGF ratio or PAPP-A; others are not yet validated, such as HTRA1, Gal-3 and CD93. In the literature, many studies analyzed the role of several protein biomarkers, but their results are contrasting. On the other hand, some non-protein biomarkers, such as miR-125b, miR-518b and miR-628-3p, seem to be linked to an increased risk of complicated pregnancy. Thus, a first trimester heterogeneous biomarkers panel containing protein and non-protein biomarkers may be more appropriate to identify and discriminate several complications that can affect pregnancies.

Placental growth factor and fetoplacental Doppler indices in combination predict preterm birth reliably in pregnancies complicated by fetal growth restriction.

To assess the association between placental biomarkers (placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio) and fetoplacental Doppler indices (umbilical artery (UA) pulsatility index (PI) and uterine artery (UtA) PI) in various combinations for predicting preterm birth (PTB) in pregnancies complicated by fetal growth restriction (FGR). This was a prospective observational cohort study, performed at Mater Mother's Hospital in Brisbane, Queensland, Australia, from May 2022 to June 2023, of pregnancies complicated by FGR and appropriate-for-gestational-age (AGA) pregnancies. Maternal serum PlGF levels, sFlt-1/PlGF ratio, UA-PI and UtA-PI were measured at 2-4-weekly intervals from recruitment until delivery. Harrell's concordance statistic (Harrell's C) was used to evaluate multivariable Cox proportional hazards regression models featuring various combinations of placental biomarkers and fetoplacental Doppler indices to ascertain the best combination to predict PTB (< 37 weeks). Multivariable Cox regression models were used with biomarkers as time-varying covariates. The study cohort included 320 singleton pregnancies, comprising 179 (55.9%) affected by FGR, defined according to a Delphi consensus, and 141 (44.1%) with an AGA fetus. In the FGR cohort, both low PlGF levels and elevated sFlt-1/PlGF ratio were associated with significantly shorter time to PTB. Low PlGF was a better predictor of PTB than was either sFlt-1/PlGF ratio or a combination of PlGF and sFlt-1/PlGF ratio (Harrell's C, 0.81, 0.78 and 0.79, respectively). Although both Doppler indices were significantly associated with time to PTB, in combination they were better predictors of PTB than was either UA-PI > 95th centile or UtA-PI > 95th centile alone (Harrell's C, 0.82, 0.75 and 0.76, respectively). Predictive utility for PTB was best when PlGF < 100 ng/L, UA-PI > 95th centile and UtA-PI > 95th centile were combined (Harrell's C, 0.88) (hazard ratio, 32.99; 95% CI, 10.74-101.32). Low maternal serum PlGF level (< 100 ng/L) and abnormal fetoplacental Doppler indices (UA-PI > 95th centile and UtA-PI > 95th centile) in combination have the greatest predictive utility for PTB in pregnancies complicated by FGR. Their assessment may help guide clinical management of these complex pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Abstract P357: Health Behaviors in Early Pregnancy Are Associated With Mid-Pregnancy Biomarkers of Placental Health and Function

Introduction: Placental blood biomarkers are dysregulated in adverse pregnancy outcomes (APO). While health behaviors are associated with APO risk, it is not well-characterized whether health behaviors impact placental blood biomarkers. Thus, we examined the associations between health behaviors and placental biomarkers of angiogenesis in mid-pregnancy. Hypothesis: Pregnant people engaging in healthier behaviors in the 1 st trimester would demonstrate more favorable 2 nd trimester concentrations of placental biomarkers. Methods: Data from 2,078 participants with available analytes from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be were included, representing an enriched sample of APO (preterm birth, preeclampsia/eclampsia, small-for-gestational age, or stillbirth; n=1,284) and 12% of those without these diagnoses (n=794). Health behaviors of physical activity, sleep, smoking, and diet assessed in the 1 st trimester were scored from 0-100 according to the Life’s Essential 8 algorithm; a higher score is more favorable. Biomarkers assayed included total endoglin, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor, placental growth factor, and soluble FMS-like tyrosine 1. The association between health behaviors and each biomarker was examined using linear (continuous) or logistic (odds of concentration below multiple of the median [MoM] cut point) regression adjusted for demographics, BMI, resilience (Connor-Davidson Scale), and perceived discrimination (Krieger Racism Scale) using a backwards stepwise approach; analyses were repeated stratified by APO status. Bonferroni-corrected significance was p&lt;0.001. Results: The overall APO rate in this enriched sample was 62%; this was significantly lower in those with ≥150 min/week compared with no physical activity (58% vs 66%, p=0.04). Lower (worse) smoking score was associated with lower (adverse) PAPP-A concentration in those who developed APO (p&lt;0.001). Higher physical activity score (healthier) was associated with lower PAPP-A concentration (adverse) regardless of APO occurrence; for every 10-point higher physical activity score, odds of PAPP-A &lt; 0.3 MoM increased 10% (OR 1.10; 95% CI 1.05, 1.16). No associations were observed between the other health behaviors and biomarkers. Conclusions: Higher levels of physical activity were associated with lower APO occurrence. In contrast, PAPP-A concentrations were lower in those with higher physical activity regardless of pregnancy outcome. Lower 2 nd trimester PAPP-A was observed in those with higher smoking exposure who developed APO. Our findings support prior work demonstrating lower risk of APO with more physical activity in pregnancy, but also indicate that PAPP-A concentrations may be sensitive to physical activity and smoking. Further work to elucidate the mechanisms of these associations is warranted.

Placental biomarkers of fetal-originated diseases

Fetal-originated diseases refer to birth defects of offspring and multiple chronic diseases in adulthood caused by abnormal embryonic development. However, due to the vulnerability of the fetus/ neonate and technical limitations, it is very difficult to carry out effective development assessment and early warning of long-term diseases in the early stages of life. It is known that the placenta is the unique link between the mother and the fetus, and its role in the occurrence and progression of fetal-originated diseases cannot be ignored. Studies have found that a variety of adverse environmental factors (such as nanoparticle exposure) cannot pass through the placental barrier, but can lead to fetal dysplasia and multi-organ development programming changes by affecting placental development, and ultimately mediate the occurrence of fetal-originated diseases. Meanwhile, some environmental factors that can pass through the placental barrier can cause placenta-fetal co-exposure, resulting in similar signaling pathways and epigenetic changes. The placenta originates from the fetus and the mother, and its development is accompanied by changes in indicators that can be objectively and quantitatively detected. These factors can be used as a biomarker to assess maternal exposure, and placental function, and to predict the developmental status and long-term disease susceptibility of offspring. To date, researchers have discovered a variety of potential placental biomarkers, and show promising application prospects. This paper reviews the recent research on placenta-related mechanisms leading to fetal-originated diseases and placental biomarkers, to provide the theoretical and experimental basis for early warning, prevention, and treatment of fetal-originated diseases.

The role of the placenta-brain axis in psychoneuroimmune programming

Gestational exposures have enduring impacts on brain and neuroimmune development and function. Perturbations of pregnancy leading to placental structure/function deficits, cell stress, immune activation, and endocrine changes (metabolic, growth factors, etc.) all increase neuropsychiatric risk in offspring. The existing literature links obstetric diseases with placental involvement to offspring neuroimmune outcomes and neurodevelopmental risk. Psychoneuroimmune outcomes in offspring brain include changes to microglia, cytokine/chemokine production, cell stress, and long-term immunoreactivity. These outcomes are altered by structural, anti-angiogenic/hypoxic, inflammatory, and metabolic diseases of the placenta. This fetal programming occurs via direct placental passage or production of factors which can act directly on fetal brain substrates, or indirectly via action of circulating factors on intermediates in the placenta. Placental neuroendocrine, vascular/angiogenic, immune, and extracellular vesicular mechanisms are detailed. These mechanisms interact within various placental and pregnancy conditions. An increased understanding of the placental origins of psychoneuroimmunology will yield dividends for human health. Identifying maternal and placental biomarkers for fetal neuroimmune health may also revolutionize early diagnosis and precision psychiatry, empowering patients to make the best healthcare decisions for their families. Targeting placental mechanisms may be a valuable approach for the prevention and mitigation of intergenerational, lifelong neuropathology.

Prenatal alcohol exposure is associated with changes in placental gene co-expression networks

Alcohol consumption during pregnancy can result in a range of adverse postnatal outcomes among exposed children. However, identifying at-risk children is challenging given the difficulty to confirm prenatal alcohol exposure and the lack of early diagnostic tools. Placental surveys present an important opportunity to uncover early biomarkers to identify those at risk. Here, we report the first transcriptome-wide evaluation to comprehensively evaluate human placental pathways altered by fetal alcohol exposure. In a prospective longitudinal birth cohort in Cape Town, South Africa, we performed bulk tissue RNAseq in placenta samples from 32 women reporting heavy drinking during pregnancy and 30 abstainers/light drinkers. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis were performed to assess associations between fetal alcohol exposure and placental gene expression patterns at a network-wide and single gene level, respectively. The results revealed altered expression in genes related to erythropoiesis and angiogenesis, which are implicated in established postnatal phenotypes related to alcohol exposure, including disruptions in iron homeostasis, growth, and neurodevelopment. The reported findings provide insights into the molecular pathways affected by prenatal alcohol exposure and highlight the potential of placental biomarkers for detecting and understanding the effects of alcohol on fetal development.

Expression of placental CD146 is dysregulated by prenatal alcohol exposure and contributes in cortical vasculature development and positioning of vessel-associated oligodendrocytes.

Recent data showed that prenatal alcohol exposure (PAE) impairs the "placenta-brain" axis controlling fetal brain angiogenesis in human and preclinical models. Placental growth factor (PlGF) has been identified as a proangiogenic messenger between these two organs. CD146, a partner of the VEGFR-1/2 signalosome, is involved in placental angiogenesis and exists as a soluble circulating form. The aim of the present study was to investigate whether placental CD146 may contribute to brain vascular defects described in fetal alcohol spectrum disorder. At a physiological level, quantitative reverse transcription polymerase chain reaction experiments performed in human placenta showed that CD146 is expressed in developing villi and that membrane and soluble forms of CD146 are differentially expressed from the first trimester to term. In the mouse placenta, a similar expression pattern of CD146 was found. CD146 immunoreactivity was detected in the labyrinth zone and colocalized with CD31-positive endothelial cells. Significant amounts of soluble CD146 were quantified by ELISA in fetal blood, and the levels decreased after birth. In the fetal brain, the membrane form of CD146 was the majority and colocalized with microvessels. At a pathophysiological level, PAE induced marked dysregulation of CD146 expression. The soluble form of CD146 decreased in both placenta and fetal blood, whereas it increased in the fetal brain. Similarly, the expression of several members of the CD146 signalosome, such as VEGFR2 and PSEN, was differentially impaired between the two organs by PAE. At a functional level, targeted repression of placental CD146 by in utero electroporation (IUE) of CRISPR/Cas9 lentiviral plasmids resulted in (i) a decrease in cortical vessel density, (ii) a loss of radial vascular organization, and (iii) a reduced density of oligodendrocytes. Statistical analysis showed that the more the vasculature was impaired, the more the cortical oligodendrocyte density was reduced. Altogether, these data support that placental CD146 contributes to the proangiogenic "placenta-brain" axis and that placental CD146 dysfunction contributes to the cortical oligo-vascular development. Soluble CD146 would represent a promising placental biomarker candidate representative of alcohol-induced neurovascular defects in neonates, as recently suggested by PlGF (patents WO2016207253 and WO2018100143).

Systemic Oxidative Stress in Severe Early-Onset Fetal Growth Restriction Associates with Concomitant Pre-Eclampsia, Not with Severity of Fetal Growth Restriction.

Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = -0.281 p = 0.004, pre-eclampsia; ρ = -0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = -0.348 p = 0.001) and diastolic blood pressure (ρ = -0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = -0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.

Aspirin for evidence-based preeclampsia prevention trial: effects of aspirin on maternal serum pregnancy-associated plasma protein A and placental growth factor trajectories in pregnancy

BackgroundThe exact mechanism by which aspirin prevents pre-eclampsia (PE) remains unclear. Its effects on serum placental biomarkers throughout pregnancy are also unknown. ObjectiveTo investigate the effects of aspirin on serum pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PlGF) trajectories using repeated measures from women at increased risk of preterm PE. Study DesignThis was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention (ASPRE) trial using repeated measures of PAPP-A and PlGF. In the trial, 1,620 women at increased risk of preterm PE were identified using the Fetal Medicine Foundation algorithm at 11-13+6 weeks, of whom 798 were randomly assigned to receive aspirin 150 mg and 822 to receive placebo daily from before 14 weeks to 36 weeks of gestation. Serum biomarkers were measured at baseline and follow-up visits at 19 to 24, 32 to 34, and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effect of aspirin on biomarker trajectories over time. ResultsOverall, there were 5,507 PAPP-A and 5,523 PlGF measurements. Raw PAPP-A values increased over time, and raw PlGF increased until 32 weeks of gestation followed by a decline. The multiple of the median (MoM) mean values of the same biomarkers were consistently below 1.0 MoM, reflecting the high-risk profile of the study population. Trajectories of mean PAPP-A and PlGF MoM values did not differ significantly between the aspirin and placebo groups (aspirin treatment by gestational age interaction p-values: 0.259 and 0.335, respectively). ConclusionsIn women at increased risk of preterm PE, aspirin 150 mg daily had no significant effects on PAPP-A or PlGF trajectories when compared to placebo.

A comparative study of performance of first trimester FMF algorithm for prediction of preeclampsia in singleton and twin pregnancies in coastal Karnataka

Preeclampsia is one of the most common disorders of pregnancy known to complicate 5-10% of all the pregnancies, and it is a component of the deadly triad (along with haemorrhage and infection), that contributes greatly to maternal morbidity and mortality rates. The prevalence of preeclampsia in twin pregnancy is 3-4 fold compared to singleton pregnancy. Timely diagnosis and prevention of this condition is therefore critical. Multiple maternal factors and placental biomarkers have shown to predict preeclampsia in singleton pregnancies. Previous Studies have shown that the proposed algorithms for preeclampsia screening in singletons can also be applied in twins, but with slight modifications and lower accuracy. To study the various parameters included in FMF screening algorithm in first trimester for preeclampsia in singleton and twin pregnancies. To find diagnostic accuracy of screening parameters to predict preeclampsia later in second and third trimester. To study sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) in singleton and twin pregnancy. This prospective observational cohort study conducted in department of Obstetrics and Gynecology, Kasturba Medial College, Hospital, Manipal. Patients were recruited from August 2021 to November 2022. A total of 295 pregnant women were included of which 255 were singleton gestation and 40 were twin gestation. All parameters mentioned in FMF algorithm were obtained between 11week to 13+6 weeks. Patients were followed until delivery for occurrence of pre-eclampsia. Individual parameters of first trimester FMF algorithm of pre-eclampsia screening were analyzed in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) in both singleton and twin study subjects and results were then compared among the groups. In this study a total of 295 pregnant women were recruited. 255 were single gestation of which 47 had preeclampsia and 40 were twin gestation of which 4 had preeclampsia. In the cohort of singleton pregnant women with pre-eclampsia, mean age was noted to be higher (32.77±4.27). They had higher BMI (mean 27.61±3.74) and first trimester MAP was also higher. Similarly, cohort of twin pregnancy with preeclampsia had higher mean of maternal age, BMI and MAP (30.33 ±4.46, 22.83 ± 2.93 and 90.40 ± 1.45 respectively). The Preeclampsia group in both singleton and twin subjects had lower serum concentration and lower MoM values of PAPP-A and PlGF while higher values of free beta HCG and uterine artery PI. Therefore the FMF algorithm for first trimester screening of preeclampsia was found to be a good predictor in both singleton and twin pregnancy. The first trimester FMF algorithm for preeclampsia screening had similar utility in the prediction of preeclampsia in both singleton and twin pregnancy with its individual parameters and combined risk model. However, its accuracy was slightly lesser among twins. Therefore, same screening model can be applicable in singleton and twin gestation.

Molecular pathways in placental-fetal development and disruption

The first trimester of pregnancy ranks high in priority when minimizing harmful exposures, given the wide-ranging types of organogenesis occurring between 4- and 12-weeks’ gestation. One way to quantify potential harm to the fetus in the first trimester is to measure a corollary effect on the placenta. Placental biomarkers are widely present in maternal circulation, cord blood, and placental tissue biopsied at birth or at the time of pregnancy termination. Here we evaluate ten diverse pathways involving molecules expressed in the first trimester human placenta based on their relevance to normal fetal development and to the hypothesis of placental-fetal endocrine disruption (perturbation in development that results in abnormal endocrine function in the offspring), namely: human chorionic gonadotropin (hCG), thyroid hormone regulation, peroxisome proliferator activated receptor protein gamma (PPARγ), leptin, transforming growth factor beta, epiregulin, growth differentiation factor 15, small nucleolar RNAs, serotonin, and vitamin D. Some of these are well-established as biomarkers of placental-fetal endocrine disruption, while others are not well studied and were selected based on discovery analyses of the placental transcriptome. A literature search on these biomarkers summarizes evidence of placenta-specific production and regulation of each biomarker, and their role in fetal reproductive tract, brain, and other specific domains of fetal development. In this review, we extend the theory of fetal programming to placental-fetal programming.

Association between adverse pregnancy outcome and placental biomarkers in the first trimester: A prospective cohort study.

To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human chorionic gonadotrophin [beta-hCG], placenta growth factor [PlGF] and soluble fms-like tyrosine kinase receptor-1 [sFlt-1]) and a range of adverse pregnancy outcomes (APOs). Prospective cohort study of nulliparous singleton pregnancy. Cambridge, UK. 4056 pregnancy outcome prediction study participants. The biomarker concentrations were measured in maternal serum at ~12 weeks of gestation. Univariable analysis of APOs was performed using logistic regression. Multivariable analysis used best subsets logistic regression with cross-validation. Pre-eclampsia (PE), small for gestational age (SGA), including severe SGA (birthweight <3rd), fetal growth restriction (FGR), preterm birth (PTB, both induced and spontaneous [iPTB and sPTB, respectively]), pre-viable loss and stillbirth, plus combinations of outcomes. Lower values of PAPP-A, PlGF and sFlt-1 and higher values of AFP were associated with FGR (OR for 1 SD higher value 0.59 [95% CI 0.48-0.74], OR 0.56 [95% CI 0.44-0.70], OR 0.68 [95% CI 0.54-0.87] and OR 1.53 [95% CI 1.25-1.88]), severe SGA (OR0.59 [95% CI 0.49-0.72], OR 0.71 [95% CI 0.57-0.87], OR 0.74 [95% CI 0.60-0.91] and OR 1.41 [95% CI 1.17-1.71]), sPTB (OR 0.61 [95% CI 0.50-0.73], OR 0.79 [95% CI 0.66-0.96], OR 0.57 [95% CI 0.47-0.70] and OR 1.41 [95% CI 1.18-1.67]) and iPTB (OR 0.72 [95% CI 0.57-0.91], OR 0.62 [95% CI 0.49-0.78], OR 0.71 [95% CI 0.56-0.90] and OR 1.44 [95% CI 1.16-1.78]), respectively. When combinations of biomarkers were assessed, PAPP-A and AFP were independently associated with severe SGA; PAPP-A alone with PE + PTB; PlGF alone with severe PE; PlGF, beta-hCG, AFP and PAPP-A with the combination of PE and SGA; AFP and sFlt-1 with sPTB; and AFP and PlGF with iPTB. Combinations of first-trimester placental biomarkers are associated with APOs. However, the patterns vary for different types of APO, indicating heterogeneity in the underlying pathophysiological pathways.

EP18.23: Placental biomarkers in the prediction of complications in pregnancy after assisted reproductive technology

EP18.23: Placental biomarkers in the prediction of complications in pregnancy after assisted reproductive technology