Growth Restricted Pregnancies Research Articles

Monitoring of maternal-fetal oxygen transfer in ex vivo full term human placenta from normal and growth restricted pregnancies.

Monitoring of maternal-fetal oxygen transfer in ex vivo full term human placenta from normal and growth restricted pregnancies.

Long-Term Maternal and Neonatal Outcomes Following Birth in Fetal Growth Restricted Pregnancies

Long-Term Maternal and Neonatal Outcomes Following Birth in Fetal Growth Restricted Pregnancies

Prognostic value of angiogenic markers in pregnancy with fetal growth restriction.

Pregnancies with fetal growth restriction (FGR) are at increased risk for pre-eclampsia. Angiogenic markers including soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by FGR, but their utility for predicting pre-eclampsia in growth-restricted pregnancies is uncertain. This study aimed to evaluate the prognostic value of angiogenic markers for predicting the development of pre-eclampsia in pregnancies with FGR and suspected pre-eclampsia. This was a retrospective study of singleton pregnancies with FGR, defined according to Delphi consensus criteria, which underwent sampling of sFlt-1 and PlGF for suspicion of pre-eclampsia at the Medical University of Vienna, Vienna, Austria, between 2013 and 2020. Women with an established diagnosis of pre-eclampsia at sampling were excluded. Cox regression analysis and logistic regression analysis were performed to evaluate the association of angiogenic markers with the development of pre-eclampsia at various timepoints. In this cohort of 93 women, pre-eclampsia was diagnosed in 14 (15.1%) women within 1 week after sampling, 21 (22.6%) within 2 weeks after sampling and 38 (40.9%) at any time after assessment. The sFlt-1/PlGF ratio consistently showed a stronger association with the development of pre-eclampsia compared to sFlt-1 or PlGF alone (pre-eclampsia within 1 week: area under the receiver-operating-characteristics curve, 0.87 vs 0.82 vs 0.72). Models including the sFlt-1/PlGF ratio were associated more strongly with pre-eclampsia hazard compared to models including sFlt-1 or PlGF alone (concordance index, 0.790 vs 0.759 vs 0.755). The risk classification capability of the sFlt-1/PlGF ratio decreased after the 2-week timepoint. The established cut-off value for the sFlt-1/PlGF ratio of < 38 was effective for ruling out pre-eclampsia within 2 weeks, with a negative predictive value of 0.933 and sensitivity of 0.952. Use of the sFlt-1/PlGF ratio is preferrable to the use of PlGF alone for the prediction of pre-eclampsia in pregnancies with FGR. Established cut-offs for ruling out the development of pre-eclampsia in the short term seem to be effective in these patients. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Placental differences between severe fetal growth restriction and hypertensive disorders of pregnancy requiring early preterm delivery: morphometric analysis of the villous tree supported by artificial intelligence

The "great obstetrical syndromes" of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether one or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways. To determine how quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent/reversed umbilical artery Doppler indices, hypertensive disorders of pregnancy, and the two conditions combined among subjects with disease severity warranting early preterm delivery. We hypothesize that trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulate that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction, with no additional effect when hypertension is concomitantly present. In this retrospective cohort study, paraffin-embedded placental tissue was obtained from four groups: [1] Severe fetal growth restriction with absent/reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, [2] Severe fetal growth restriction with absent/reversed umbilical artery Doppler indices and no hypertension,[3] Gestational age-matched, appropriately grown pregnancies with hypertensive disease, and [4] Gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed followed by artificial intelligence-driven morphometric analyses. Number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled with linear regression. Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi, 95% CI: [-467, -98], p<0.01), smaller stem villous area (-4.3 mm2, 95% CI: [-7.3, -1.2], p<0.01), and fewer stem villous vessels (-4967 stem villous vessels, 95% CI [-8501, -1433], p<0.01), with no difference in total vascular area. In contrast, placental abnormalities in severe growth restriction were limited to terminal villi, with global decreases in number of villi (-873 terminal villi, 95% CI: [-1501, -246], p<0.01), villous area (-1.5 mm2, 95% CI: [-2.7, -0.4], p<0.01), number of blood vessels (-5165 terminal villous vessels, 95% CI: [-8201, -2128], p<0.01), and vascular area (-0.6 mm2, 95% CI: [-1.1, -0.1], p=0.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state. Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent/reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions with the combination of growth restriction and hypertension, suggesting that distinct pathophysiologic pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to result in more severe pathologic consequences. Delineating mechanisms underlying the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.

Umbilical–portal–systemic venous shunt and intrauterine growth restriction: an inquiry from a prospective study

BackgroundThe investigation of the fetal umbilical-portal venous system is based on the premise that congenital anomalies of this system may be related to adverse perinatal outcomes. Several retrospective small studies have reported a well-established association between umbilical–portal–systemic venous shunts and fetal growth restriction. However, the prevalence of portosystemic shunts in the fetal growth restricted population is yet to be determined. ObjectivesThe aims of this study were:1. To determine the prevalence of fetal umbilical–portal–systemic venous shunts in pregnancies complicated by fetal growth restriction.2. To compare the perinatal and neonatal outcome of fetal growth restriction pregnancies with and without umbilical–portal–systemic venous shunts. Study DesignA prospective cross-sectional study of pregnancies diagnosed with fetal growth restriction, as defined by the Society for Maternal-Fetal Medicine fetal growth restriction guidelines. All participants underwent a detailed anomaly scan supplemented with a targeted scan of the fetal portal system. Venous shunts were diagnosed using color Doppler mode. The perinatal outcomes of fetal growth restriction pregnancies with and without umbilical–portal–systemic venous shunts were compared. ResultsOne hundred and fifty cases of fetal growth restriction were recruited. The prevalence of umbilical–portal–systemic venous shunts in our cohort was 9.3% (n=14). Compared to the control group (fetal growth restriction without umbilical–portal–systemic venous shunts, n=136), the study group had a significantly lower mean gestational age at time of fetal growth restriction diagnosis [29.7 (±5.6) vs. 32.47 (±4.6) weeks of gestation, p=0.036] as well as an earlier gestational week at delivery [33.50 (±6.0) vs. 36.13 (±2.8), p=0.005]. The study group had a higher rate of fetal death (21.4% vs. 0.7%, p<0.001) and accordingly a lower rate of live births (71.4% vs. 95.6%, p=0.001). Associated additional fetal vascular anomalies were significantly more prevalent in the study group compared to controls (35.7% vs. 4.4%, respectively, p=<0.001). The rate of other associated anomalies was similar. The study group had a significantly lower rate of abnormal uterine artery Doppler indices (0% vs. 40.4% p=0.011) and a higher rate of abnormal ductus venosus Doppler indices (64.3% vs. 23% p=0.001). There were no cases of hypertensive disorders of pregnancy in the study group compared to 12.5% in the control group (p=0.16). Other perinatal and neonatal outcomes were comparable. ConclusionsUmbilical–portal–systemic venous shunt is a relatively common finding in growth restricted fetuses. Compared to fetal growth restriction pregnancies with a normal portal system, these pregnancies complicated by FGR and umbilical–portal–systemic venous shunt are associated with different Doppler flow pattern, increased risk for fetal death, earlier presentation of fetal growth restriction, lower gestational age at delivery, additional congenital vascular anomalies and a lower rate of pregnancy induced hypertensive disorders. Meticulous sonographic evaluation of the portal system should be considered in the prenatal workup of fetal growth restriction, as umbilical–portal–systemic venous shunts may have implications on perinatal outcome.

Maternal serum fatty acid binding protein-4 level is upregulated in fetal growth restriction with abnormal Doppler flow patterns.

This study aimed to determine fatty acid binding protein-4 (FABP-4) concentrations in maternal serum of fetal growth restriction (FGR) pregnancies and controls of normal pregnancies. Furthermore, we hypothesized that the alterations in FABP-4 levels might correlate with FGR severity. We performed this prospective case-control study with 83 pregnant women. The study groups included 26 FGR pregnancies without abnormal fetal Doppler flow patterns and 25 pregnancies complicated with FGR accompanied by abnormal fetal Doppler flow patterns. The median serum FABP-4 concentrations were significantly higher in the FGR cases with abnormal Doppler flow pattern group (2.09 ng/mL) than in the FGR cases without abnormal Doppler flow pattern group (1.62 ng/mL) and the control group (1.20 ng/mL, p < 0.001). A significant negative correlation was observed between maternal serum FABP-4 levels and time to birth from blood sample collection (r = -0.356 and p = 0.001), gestational week at birth (r = -0.386 and p < 0.001), and birth weight (r = -0.394 and p < 0.001). A 1.35 ng/mL cut-off value of serum FABP-4 level could be used to discriminate FGR cases with a 78.4% sensitivity and 60.6% specificity. The optimal cut-off value of FABP-4 levels as an indicator for the diagnosis of FGR with abnormal Doppler flow pattern was estimated to be 1.76 ng/mL, which yielded a sensitivity of 84.0% and a specificity of 75.8%. FABP-4 is a crucial biomarker in the diagnosis and determining the severity of pregnancies with restricted fetal growth. We consider that FABP-4 is a powerful, reliable, and unique biomarker to diagnose FGR pregnancies.

EP18.17: Prediction of pre‐eclampsia and fetal growth restriction in pregnancies with systemic lupus erythematosus

EP18.17: Prediction of pre‐eclampsia and fetal growth restriction in pregnancies with systemic lupus erythematosus

OP15_6. Effect of pentaerythrityltetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at mid gestation – a double blinded randomised multicentre trial

OP15_6. Effect of pentaerythrityltetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at mid gestation – a double blinded randomised multicentre trial

Silicone breast implants may contribute to early-onset fetal growth restriction.

There are many studies showing that silicone breast implants may affect lactation, but few analyzed whether these implants affect placentation. We observed that many mothers with growth-restricted pregnancies had inflammatory conditions, such as silicone breast implants or giardiasis. This single-center cohort study assessed the prevalence of inflammatory conditions in normotensive growth-restricted singleton pregnancies. Next, we stratified the patients according to the presence or absence of silicone breast implants, to determine whether these implants influence fetal growth restriction onset or severity. Twelve (32%) of the 38 participants underwent cosmetic breast augmentation 4-18years before pregnancy. Half of the patients with and 38% without silicone breast implants had giardiasis. Half of the mothers with and 35% without silicone breast implants had autoantibodies. Silicone breast implants were associated with a 70% increased risk of fetal growth restriction before 32weeks' gestation (95% confidence interval [CI], 1.2-2.5). Fetal growth restriction was diagnosed significantly earlier in mothers with than in those without silicone breast implants, respectively at 27 (95% CI, 25-30) and 30weeks' gestation (95% CI, 29-32). Silicone breast implants also tripled the risk of fetuses being below the third percentile, but the difference was not significant. Our results suggest that the association of inflammatory conditions, such as silicone breast implants, giardiasis, and autoantibodies may contribute to placental insufficiency. Silicone breast implants older than four years increased the risk of early-onset fetal growth restriction. Studies with large samples are needed to validate our findings and define whether silicone-related fetal growth restriction should be included in autoimmune/inflammatory syndrome induced by adjuvants (ASIA) criteria. Key Points • Fetal growth restriction (FGR), responsible for 30% of stillbirths, is the most common cause of prematurity and intrapartum asphyxia. • In this study, including 38 mothers with normotensive FGR, all participants had 2-4 inflammatory conditions, such as giardiasis, sinusitis, candidiasis, dysbiosis, extreme fear or autoantibodies. • Silicone breast implants were associated with a 70% increased risk of fetal growth restriction before 32 weeks' gestation. • FGR was diagnosed at 27 weeks' gestation (95% CI, 25-30) in mothers with and at 30 weeks' gestation (95% CI, 29-32) in mothers without silicone breast implants.

Reduced Endothelial Progenitor Cells: A Possible Biomarker for Idiopathic Fetal Growth Restriction in Human Pregnancies.

Circulating endothelial progenitor cells (EPCs) may be necessary throughout pregnancy by ensuring proper placentation and embryonic growth. The lack of standardized EPC quantification techniques has prevented conclusive proof of an increase in EPC during pregnancy. The purpose of this study was to determine whether EPC levels change for healthy and idiopathic fetal growth restriction (FGR) pregnancies. The study population consisted of 48 healthy pregnant females with no previous history of IUGR (10 in the first trimester, 15 in the second, and 23 in the third), 48 women with pregnancy complicated by idiopathic FGR, and 15 non-pregnant women. By using flow cytometry, EPCs in maternal blood were recognized as CD45dim/CD34/KDR cells. ELISA was used to measure plasmatic cytokines. We ascertained a progressive rise in EPCs in healthy pregnancies that was apparent in the first but more pronounced in the third trimester. At comparable gestational ages, FGR-complicated pregnancies had impaired EPC growth. Placental growth factor and stromal-derived factor-1 levels in the blood were significantly lower in FGR than in healthy pregnancies, which may have contributed to the degradation of the EPCs. The count in EPCs might hold considerable promise toward developing a peculiar authentication marker for observing pregnancies, and could be the focus of cutting-edge tactics for the prognosis and treatment of FGR pregnancies.

Impact of Chorionic Somatomammotropin In Vivo RNA Interference Phenotype on Uteroplacental Expression of the IGF Axis.

While fetal growth is dependent on many factors, optimal placental function is a prerequisite for a normal pregnancy outcome. The majority of fetal growth-restricted (FGR) pregnancies result from placental insufficiency (PI). The insulin-like growth factors (IGF1 and IGF2) stimulate fetal growth and placental development and function. Previously, we demonstrated that in vivo RNA interference (RNAi) of the placental hormone, chorionic somatomammotropin (CSH), resulted in two phenotypes. One phenotype exhibits significant placental and fetal growth restriction (PI-FGR), impaired placental nutrient transport, and significant reductions in umbilical insulin and IGF1. The other phenotype does not exhibit statistically significant changes in placental or fetal growth (non-FGR). It was our objective to further characterize these two phenotypes by determining the impact of CSH RNAi on the placental (maternal caruncle and fetal cotyledon) expression of the IGF axis. The trophectoderm of hatched blastocysts (9 days of gestation, dGA) were infected with a lentivirus expressing either a non-targeting sequence (NTS RNAi) control or CSH-specific shRNA (CSH RNAi) prior to embryo transfer into synchronized recipient ewes. At ≈125 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies. Nutrient uptakes were determined, and tissues were harvested at necropsy. In both CSH RNAi non-FGR and PI-FGR pregnancies, uterine blood flow was significantly reduced (p ≤ 0.05), while umbilical blood flow (p ≤ 0.01), both uterine and umbilical glucose and oxygen uptakes (p ≤ 0.05), and umbilical concentrations of insulin and IGF1 (p ≤ 0.05) were reduced in CSH RNAi PI-FGR pregnancies. Fetal cotyledon IGF1 mRNA concentration was reduced (p ≤ 0.05) in CSH RNAi PI-FGR pregnancies, whereas neither IGF1 nor IGF2 mRNA concentrations were impacted in the maternal caruncles, and either placental tissue in the non-FGR pregnancies. Fetal cotyledon IGF1R and IGF2R mRNA concentrations were not impacted for either phenotype, yet IGF2R was increased (p ≤ 0.01) in the maternal caruncles of CSH RNAi PI-FGR pregnancies. For the IGF binding proteins (IGFBP1, IGFBP2, IGFBP3), only IGFBP2 mRNA concentrations were impacted, with elevated IGFBP2 mRNA in both the fetal cotyledon (p ≤ 0.01) and maternal caruncle (p = 0.08) of CSH RNAi non-FGR pregnancies. These data support the importance of IGF1 in placental growth and function but may also implicate IGFBP2 in salvaging placental growth in non-FGR pregnancies.

Determination of maternal serum pro-inflammatory cytokine changes in intrauterine growth restriction.

To evaluate maternal serum inflammatory marker changes in intrauterine growth restriction (IUGR) pregnancies. 50 healthy pregnant women and 50 patients diagnosed with IUGR were enrolled. Maternal serum high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 levels were measured before delivery and neonatal outcomes were evaluated. Birth weight, Apgar scores, and cord blood gas pH were lower in the IUGR group (p<0.001, p<0.001, p<0.001 and p=0.006, respectively). While the levels of ESR, hsCRP, IL-6, and TNF-α were higher, the IL-10 level was found to be lower in the IUGR group (p<0.001, p=0.033, p<0.001, p=0.004 and p<0.001, respectively). As ESR, hsCRP, and IL-6 levels increased, birth weight, Apgar scores, and cord blood gas pH decreased (p<0.001, p<0.001, p<0.001, p<0.001, p=0.02, p=0.002, p=0.001, p=0.03, p<0.001, p<0.001, p<0.001 and p=0.02, respectively). As TNF-α level increased, only birth weight and Apgar score at the 1st minute decreased (p=0.006 and p=0.048, respectively). As IL-10 level decreased, birth weight, Apgar scores, and cord blood gas pH decreased (p<0.001 for all). IL-6 (>3.2 pg/ml) had a sensitivity of 100%, specificity of 100%, PPV of 100% and NPV of 100%. While birth weight, Apgar score and cord blood pH decreased in IUGR cases, ESR, hsCRP, IL-6 and TNF-α levels increased. Combined measurement of these markers can be used for the diagnosis of IUGR.

A STUDY ON DOPPLER ULTRASOUND PARAMETERS IN FETAL GROWTH RESTRICTED CASES AND ITS RELATION WITH PERINATAL OUTCOME

Introduction - There is signicant maternal and perinatal mortality and morbidity in Fetal Growth Restriction pregnancies. There are chances of increased fetal hypoxia , asphyxia , meconium aspiration syndrome , macrosomia , low birth weight , hypoglycaemia ,still births and even neonatal death. The present study was being conducted in light of the crucial role that doppler examination plays in early detection of FGR cases and possible neonatal morbidity and mortality through prompt management. The present st Aim And Objectives - udy was designed to clinically correlate the ndings of doppler ultrasound in clinically suspected Fetal Growth Restriction cases with perinatal outcome. The objective was to study the doppler parameters in clinically suspected Fetal Growth Restriction cases and to relate with their perinatal outcome. Materials and Method – This study included 80 singleton clinically suspected FGR cases attending Jorhat Medical College and Hospital. It was a hospital based observational Cross sectional study. Flow velocity waveforms, the resistance index (R.I.), pulsatility index (P.I.), systolic/diastolic ratio (S/D) of the above vessels were noted.. Cerebro-placental ratio or MCA/UA P.I. ratio was also noted. The ndings of the last week of delivery were correlated with the perinatal outcomes. In the present study, the ndings of AED Results – F and REDF were associated with signicant morbidity and mortality. All babies with AEDF and REDF had succumbed to death. Considering cerebro-placental ratio is better than UA PI and MCA PI alone. Because CPR incorporates data not only on the placental side but also the fetal response. Additional uterine artery Doppler evaluation is also helpful in predicting adverse pregnancy outcome. Multi vessel colour doppler ultrasound are Conclusion – important monitoring tools in patients with FGR to identify compromised in utero and to take timely appropriate action

ASSOCIATION BETWEEN MATERNAL BASAL GLUCOSE LEVEL AND INTRAUTERINE GROWTH RESTRICTION: A COMPARATIVE CROSS-SECTIONAL STUDY

Background: Intrauterine life is the most pivotal period of development that determines vital outcomes in postnatal life. Diabetes Mellitus may lead to disturbed fetal growth and maternal vasculopathy resulting in placental insufficiency with subsequent development of intrauterine growth restriction (IUGR). This study aims to find an association between hyperglycemia and the risk of IUGR, comparing pregnancies with IUGR with those with adequate for gestational age pregnancies.&#x0D; Methods: This cross sectional study was conducted in Federal Post Graduate Medical Institute (FPGMI) from January 2015 to January 2016, including 106 pregnant women using non-probability convenient sampling technique. Participants were divided into two groups: Group A comprises of pregnant women with adequate for gestational age pregnancies (n=53) and groups B includes pregnant women with intrauterine growth restricted pregnancies (n=53). Random blood sugar level was estimated by glucose/oxidase test and IUGR was confirmed by ultrasonography at 28-35 weeks of gestation. Shapiro-Wilk test was used to examine data normality and independent t-test was used to compare statistically significant difference. A p- value of &lt;0.05 was considered significant.&#x0D; Results: Mean basal sugar level of group A was 98.9 ± 7.1 mg/dL and that of group B was 97.9 ± 6.0mg/dL. This mean difference was not statistically significant (p-value= 0.566).&#x0D; Conclusion: We found no statistically significant association between raised maternal basal glucose level and the occurrence of intrauterine growth restriction at 28-35 weeks of pregnancy.

Comparison of Outcomes of Fetal Growth Restricted Pregnancies by Presence of Proteinuria

Comparison of Outcomes of Fetal Growth Restricted Pregnancies by Presence of Proteinuria

Physician recommendations for physical activity in complicated growth restricted pregnancies

Physician recommendations for physical activity in complicated growth restricted pregnancies

Assessment of Fetal Thymus Size in Small for Gestational Age and Growth Restricted Fetuses

Objective: The purpose of this study was to analyze the fetal thymus size by sonography in healthy, small for gestational age (SGA), and fetal growth restriction (FGR) pregnancies and investigate if there is a difference between healthy fetuses and those with growth restriction. &#x0D; Study Design: The thymic-thoracic ratio (TTR), transverse diameter, and perimeter of the fetal thymus were prospectively measured in SGA and FGR pregnancies between the gestational ages of 20 and 37 weeks and compared with healthy controls. Fetal abdominal circumference (AC) or estimated fetal weight (EFW)

The management of neonatal herpes simplex virus infection in a small for gestational age neonate - Case report

Neonatal herpes simplex virus infections are rare, normally acquired through vertical transmission in the peripartum period, usually manifesting before 14 days of life and being identified on the basis of history, clinical and laboratory evaluation. We present the case of a small for gestational age male infant born at 38 weeks gestational age with neonatal herpes simplex virus infection. The diagnosis was delayed because the attention was focused on an unidentified bacterial infection. In cases where a clinical picture suggestive of infection is described, with laboratory tests that support the diagnosis of infection, but with cultures that do not highlight bacterial or mycological agents, we must not forget about viral agents, specifically among those newborns from intrauterine growth restricted pregnancies. Neonatal HSV infections can be present even in the absence of herpetic vesicles in the newborn and even if the mother is asymptomatic.

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function.

Endothelial protein C receptor is increased in preterm preeclampsia and fetal growth restriction.

Placental dysfunction is the leading cause of both preeclampsia and fetal growth restriction. This study aimed to characterize endothelial protein C receptor (EPCR) in preterm preeclampsia, term preeclampsia, and fetal growth restriction (defined by delivery of a small for gestational age [SGA] infant [<10% birthweight centile]) and examine its regulation in primary syncytiotrophoblast. Placental EPCR mRNA and protein were significantly increased in patients with preterm preeclampsia (<34 weeks gestation) compared to gestation-matched controls (p < .0001). In the plasma, EPCR was also significantly elevated (p=.01) in established preterm preeclampsia while its substrate, protein C (PC) was significantly reduced (p=.0083). Placentas from preterm small for gestational age (SGA) cases, had elevated EPCR mRNA expression (p < .0001) relative to controls. At 36 weeks, no significant changes in plasma EPCR were detected in samples from patients destined to develop preeclampsia or deliver an SGA infant at term. In terms of syncytiotrophoblast, hypoxia significantly increased EPCR mRNA expression (p=.008), but Tumor Necrosis Factor Alpha (TNF-α) decreased EPCR mRNA. Interleukin-6 (IL-6) had no significant effect on EPCR mRNA expression. When isolated syncytiotrophoblast was treated with metformin under hypoxia (1% O2 ) or normoxia (8% O2 ), EPCR mRNA expression was significantly reduced (p=.008) relative to control. In conclusion, EPCR is markedly elevated in the placenta and the circulation of patients with established preterm preeclampsia and placental increases may be associated with hypoxia. Additionally, fetal growth-restricted pregnancies (as defined by the delivery of an SGA infant) also demonstrated elevated placental EPCR.