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Fondos FEDER, Objective To analyze the ability to predict perinatal survival and severe neonatal morbidity of cases with early-onset fetal growth restriction (eoFGR) using maternal variables, ultrasound parameters and angiogenic markers at the time of diagnosis. Methods This was a prospective observational study in a cohort of singleton pregnancies with a diagnosis of eoFGR (< 32 weeks of gestation). At diagnosis of eoFGR, complete assessment was performed, including ultrasound examination (anatomy, biometry and Doppler assessment) and maternal serum measurement of the angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). Logistic regression models for the prediction of perinatal survival (in cases diagnosed at < 28 weeks) and severe neonatal morbidity (in all liveborn cases) were calculated. Results In total, 210 eoFGR cases were included, of which 185 (88.1%) survived perinatally. The median gestational age at diagnosis was 27 + 0 weeks. All cases diagnosed at ≥ 28 weeks survived. In cases diagnosed < 28 weeks, survivors (vs non-survivors) had a higher gestational age (26.1 vs 24.4 weeks), estimated fetal weight (EFW; 626 vs 384 g), cerebroplacental ratio (1.1 vs 0.9), PlGF (41 vs 18 pg/mL) and PlGF multiples of the median (MoM; 0.10 vs 0.06) and lower sFlt-1/PlGF ratio (129 vs 479) at the time of diagnosis (all P < 0.001). The best combination of two variables for predicting perinatal survival was provided by EFW and PlGF MoM (area under the receiver-operating-characteristics curve (AUC), 0.84 (95% CI, 0.75–0.92)). These were also the best variables for predicting severe neonatal morbidity (AUC, 0.73 (95% CI, 0.66–0.80)). Conclusions A model combining EFW and maternal serum PlGF predicts accurately perinatal survival in eoFGR cases diagnosed before 28 weeks of gestation. Prenatal prediction of severe neonatal morbidity in eoFGR cases is modest regardless of the model used. © 2022 The Authors. Ultrasound in Obstetrics & Gynecolog, European Commission, Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III (España), Depto. de Salud Pública y Materno - Infantil, Fac. de Medicina, TRUE, pub

Maternal reports of decreased fetal movement (DFM) are a common reason to present to maternity care and are associated with stillbirth and other adverse outcomes. Promoting awareness of fetal movements and prompt assessment of DFM has been recommended to reduce stillbirths. However, evidence to guide clinical management of such presentations is limited. Educational approaches to increasing awareness of fetal movements in pregnant women and maternity care providers with the aim of reducing stillbirths have recently been evaluated in a several large clinical trials internationally. The International Stillbirth Alliance Virtual Conference in Sydney 2021 provided an opportunity for international experts in fetal movements to share reports on the findings of fetal movement awareness trials, consider evidence for biological mechanisms linking DFM and fetal death, appraise approaches to clinical assessment of DFM, and highlight research priorities in this area. Following this workshop summaries of the sessions prepared by the authors provide an overview of understandings of fetal movements in maternity care at the current time and highlights future directions in fetal movement research.

Objective To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small-for-gestational age (SGA) according to estimated fetal weight < 10th percentile on twin or singleton growth charts. Methods NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first-trimester crown–rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions. Results The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6–4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4–4.7)). Conclusions When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth-related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons. © 2023 International Society of Ultrasound in Obstetrics an, Objective: To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small-for-gestational age (SGA) according to estimated fetal weight < 10th percentile on twin or singleton growth charts. Methods: NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first-trimester crown–rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions. Results: The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6–4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4–4.7)). Conclusions: When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth-related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons.

CRUE-CSIC (Acuerdos Transformativos 2022), Objective To analyze the ability to predict perinatal survival and severe neonatal morbidity of cases with early-onset fetal growth restriction (eoFGR) using maternal variables, ultrasound parameters and angiogenic markers at the time of diagnosis. Methods This was a prospective observational study in a cohort of singleton pregnancies with a diagnosis of eoFGR (< 32 weeks of gestation). At diagnosis of eoFGR, complete assessment was performed, including ultrasound examination (anatomy, biometry and Doppler assessment) and maternal serum measurement of the angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). Logistic regression models for the prediction of perinatal survival (in cases diagnosed at < 28 weeks) and severe neonatal morbidity (in all liveborn cases) were calculated. Results In total, 210 eoFGR cases were included, of which 185 (88.1%) survived perinatally. The median gestational age at diagnosis was 27 + 0 weeks. All cases diagnosed at ≥ 28 weeks survived. In cases diagnosed < 28 weeks, survivors (vs non-survivors) had a higher gestational age (26.1 vs 24.4 weeks), estimated fetal weight (EFW; 626 vs 384 g), cerebroplacental ratio (1.1 vs 0.9), PlGF (41 vs 18 pg/mL) and PlGF multiples of the median (MoM; 0.10 vs 0.06) and lower sFlt-1/PlGF ratio (129 vs 479) at the time of diagnosis (all P < 0.001). The best combination of two variables for predicting perinatal survival was provided by EFW and PlGF MoM (area under the receiver-operating-characteristics curve (AUC), 0.84 (95% CI, 0.75–0.92)). These were also the best variables for predicting severe neonatal morbidity (AUC, 0.73 (95% CI, 0.66–0.80)). Conclusions A model combining EFW and maternal serum PlGF predicts accurately perinatal survival in eoFGR cases diagnosed before 28 weeks of gestation. Prenatal prediction of severe neonatal morbidity in eoFGR cases is modest regardless of the model used. © 2022 The Authors. Ultrasound in Obstetrics & Gynecolog, Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (FEDER), Depto. de Salud Pública y Materno - Infantil, Fac. de Medicina, TRUE, pub

The extracellular matrix (ECM) in the endometrium plays a crucial role in mammalian pregnancy. We have shown that versican secreted from the endometrial epithelium promotes embryo implantation. Versican is a proteoglycan, a major player in the provisional matrix, and versikine, its N-terminal fragment cleaved by ADAMTS proteinases, serves as a bioactive molecule. Here, since versican expression in the placenta was dynamically altered in humans and mice, we investigated the role of versican in pregnancy using uterine-specific Vcan deletion mice (uKO mice) and ADAMTS-resistant versican expressing mice (V1R mice). uKO mice exhibited insufficient spiral artery dilation, followed by fetal growth restriction and maternal hypertension. Further analysis revealed impaired proliferation of tissue-resident natural killer cells required for spiral artery dilation. V1R mice showed the same results as the control, eliminating the involvement of versikine. Our results provide a new concept that versican, one factor of ECM, contributes to placentation and following fetal growth.

BACKGROUND: On the basis of available data, at least 1 ultrasound assessment of pregnancies recovering from SARS-CoV-2 infection is recommended. However, reports on prenatal imaging findings and potential associations with neonatal outcomes following SARS-CoV-2 infection in pregnancy have been inconclusive. OBJECTIVE: This study aimed to describe the sonographic characteristics of pregnancies after confirmed SARS-CoV-2 infection and assess the association of prenatal ultrasound findings with adverse neonatal outcomes. STUDY DESIGN: This was an observational prospective cohort study of pregnancies diagnosed with SARS-CoV-2 by reverse transcription polymerase chain reaction between March 2020 and May 2021. Prenatal ultrasound evaluation was performed at least once after diagnosis of infection, with the following parameters measured: standard fetal biometric measurements, umbilical and middle cerebral artery Dopplers, placental thickness, amniotic fluid volume, and anatomic survey for infection-associated findings. The primary outcome was the composite adverse neonatal outcome, defined as ≥1 of the following: preterm birth, neonatal intensive care unit admission, small for gestational age, respiratory distress, intrauterine fetal demise, neonatal demise, or other neonatal complications. Secondary outcomes were sonographic findings stratified by trimester of infection and severity of SARS-CoV-2 infection. Prenatal ultrasound findings were compared with neonatal outcomes, severity of infection, and trimester of infection. RESULTS: A total of 103 SARS-CoV-2-affected mother-infant pairs with prenatal ultrasound evaluation were identified; 3 cases were excluded because of known major fetal anomalies. Of the 100 included cases, neonatal outcomes were available in 92 pregnancies (97 infants); of these, 28 (29%) had the composite adverse neonatal outcome, and 23 (23%) had at least 1 abnormal prenatal ultrasound finding. The most common abnormalities seen on ultrasound were pla

Microplastics can enter the human body via direct body contact or the food chain, increasing the likelihood of adverse impacts on pregnancy and fetal development. We investigated the potential effects and modes of action of polystyrene nanoplastics (PS-NPs) in placenta and fetus using mice as a model species. Maternal PS-NP exposure (100 nm; 1 and 10 mg/L) via drinking water induced a significant decline in fetal weights at the higher exposure concentration. Abnormal morphologies of cells in the placenta and fetus were observed after exposure. For the placenta, transcriptomic analyses indicated that PS-NPs significantly disturbed cholesterol metabolism and complement and coagulation cascades pathways. Metabolomics showed appreciable metabolic disorders, particularly affecting sucrose and daidzein concentrations. For the fetal skeletal muscle, transcriptomics identified many significantly regulated genes, involving muscle tissue development, lipid metabolism, and skin formation. Transcriptomic analysis of the placenta and fetal skeletal muscle at the high PS-NP concentration showed that APOA4 and its transcriptional factors, facilitating cholesterol transportation, were significantly regulated in both tissues. Our study revealed that PS-NPs caused fetal growth restriction and significantly disturbed cholesterol metabolism in both placenta and fetus, offering new insights into the mechanisms underlying the placental and fetal effects in mice exposed to PS-NPs.

Background: several studies have demonstrated that angiogenic markers can improve the clinical management of hypertensive disorders (HDs) and fetal growth restriction (FGR) in singleton pregnancies, but few studies have evaluated the performance of these tests in multiple pregnancies. Our aim was to investigate the role of soluble fms-like tyrosine kinase 1 (sFlt-1) in predicting adverse obstetric outcomes in hospitalized multiple pregnancies with HD (preeclampsia/gestational hypertension/uncontrolled chronic hypertension) and/or FGR in one or more fetuses. Methods: A retrospective analysis of multiple pregnancies with HD/FGR occurring after the 20th gestational week. Pregnant women were divided into two groups: women with high levels of sFlt-1 and those with low levels of sFlt-1. A value of sFlt-1 greater than or equal to 15,802 pg/mL was considered arbitrarily high, as it is equivalent to two times the 90th percentile expected in an uncomplicated full-term singleton pregnancy based on data from a prospective multicenter study (7901 pg/mL). Results: The cohort included 39 multiple pregnancies. There were no cases of birth <34 weeks, HELLP syndrome, ICU admission, and urgent cesarean sections for HD/FGR complications reported among women with low levels of sFlt-1. Conclusions: A cut-off value of sFlt-1 ≥ 15,802 pg/mL could represent a valuable tool for predicting adverse obstetric outcomes in multiple pregnancies hospitalized for HD/FGR disorders, regardless of gestational age and chorionicity.

Background: Adenomyosis is a benign gynecologic condition arising from the uterine junctional zone. Recent studies suggest a relationship between adenomyosis and adverse obstetrical outcomes, but evidence remains conflicting. There is no large-scale study investigating obstetrical outcomes in women with adenomyosis using the gold standard of histopathologic diagnosis. Objective: This study aimed to investigate the prevalence of adverse obstetrical and neonatal outcomes in women with histopathologic adenomyosis and that of the general (Dutch) population. Study design: This retrospective population-based study used 2 Dutch national databases (Perined, the perinatal registry, and the nationwide pathology databank [Pathologisch Anatomisch Landelijk Geautomiseerd Archief], from 1995 to 2018) to compare obstetrical outcomes in women before histopathologic adenomyosis diagnosis to the general Dutch population without registered histopathologic adenomyosis. The adjusted odds ratios (95% confidence interval) were calculated for adverse obstetrical outcomes. The outcomes were adjusted for maternal age, parity, ethnicity, year of registered birth, induction of labor, hypertensive disorders in previous pregnancies, multiple gestation, and low socioeconomic status. Results: The pregnancy outcomes of 7925 women with histopathologic adenomyosis were compared with that of 4,615,803 women without registered adenomyosis. When adjusted for confounders, women with adenomyosis had adjusted odds ratios of 1.37 (95% confidence interval, 1.25-1.50) for hypertensive disorders, 1.37 (95% confidence interval, 1.25-1.51) for preeclampsia, 1.15 (95% confidence interval, 1.07-1.25) for small-for-gestational-age infants, 1.54 (95% confidence interval, 1.41-1.68) for emergency cesarean delivery, 1.24 (95% confidence interval, 1.12-1.37) for failure to progress, 1.29 (95% confidence interval, 1.10-1.48) for placental retention, and 1.23 (95% confidence interval, 1.10-1.38

Background It is a matter of debate whether 1 universal standard, such as the International Fetal and Newborn Growth Consortium for the 21st Century standard, can be applied to all populations. Objective The primary objective was to establish a Danish newborn standard based on the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard to compare the percentiles of these 2 standards. A secondary objective was to compare the prevalence and risk of fetal and neonatal deaths related to small for gestational age defined by the 2 standards when used in the Danish reference population. Study Design This was a register-based nationwide cohort study. The Danish reference population included 375,318 singletons born at 33 to 42 weeks of gestation in Denmark between January 1, 2008, and December 31, 2015. The Danish standard cohort included 37,811 newborns who fulfilled the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard. Birthweight percentiles were estimated using smoothed quantiles for each gestational week. The outcomes included birthweight percentiles, small for gestational age (defined as a birthweight of 3rd percentile), and adverse outcomes (defined as either fetal or neonatal death). Results At all gestational ages, the Danish standard median birthweights at term were higher than the International Fetal and Newborn Growth Consortium for the 21st Century standard median birthweights: 295g for females and 320 g for males. Therefore, the estimates of the prevalence rate of small for gestational age within the entire population were different: 3.9% (n=14,698) using the Danish standard vs 0.7% (n=2640) using the International Fetal and Newborn Growth Consortium for the 21st Century standard. Accordingly, the relative risk of fetal and neonatal deaths among small-for-gestational-age fetuses differed by SGA status defined by the different standar, Background: It is a matter of debate whether 1 universal standard, such as the International Fetal and Newborn Growth Consortium for the 21st Century standard, can be applied to all populations. Objective: The primary objective was to establish a Danish newborn standard based on the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard to compare the percentiles of these 2 standards. A secondary objective was to compare the prevalence and risk of fetal and neonatal deaths related to small for gestational age defined by the 2 standards when used in the Danish reference population. Study Design: This was a register-based nationwide cohort study. The Danish reference population included 375,318 singletons born at 33 to 42 weeks of gestation in Denmark between January 1, 2008, and December 31, 2015. The Danish standard cohort included 37,811 newborns who fulfilled the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard. Birthweight percentiles were estimated using smoothed quantiles for each gestational week. The outcomes included birthweight percentiles, small for gestational age (defined as a birthweight of 3rd percentile), and adverse outcomes (defined as either fetal or neonatal death). Results: At all gestational ages, the Danish standard median birthweights at term were higher than the International Fetal and Newborn Growth Consortium for the 21st Century standard median birthweights: 295g for females and 320 g for males. Therefore, the estimates of the prevalence rate of small for gestational age within the entire population were different: 3.9% (n=14,698) using the Danish standard vs 0.7% (n=2640) using the International Fetal and Newborn Growth Consortium for the 21st Century standard. Accordingly, the relative risk of fetal and neonatal deaths among small-for-gestational-age fetuses differed by SGA status defined by the different standards (4.4 [Danish standard] vs 9.6 [In

Objective To evaluate the role of antenatal administration of corticosteroids for fetal lung maturation on the short-term perinatal outcome of pregnancy complicated by late fetal growth restriction (FGR).Methods This cohort study was a secondary analysis of a multicenter prospective observational study, the TRUFFLE-2 feasibility study, conducted between 2017 and 2018 in 33 European perinatal centers. The study included women with a singleton pregnancy from 32 + 0 to 36 + 6 weeks of gestation with a fetus considered at risk for FGR, defined as estimated fetal weight (EFW) and/or fetal abdominal circumference < 10(th) percentile, or umbilicocerebral ratio (UCR) >= 95(th) percentile or a drop of more than 40 percentile points in abdominal circumference measurement from the 20-week scan. For the purposes of the current study, we identified women who received a single course of steroids to improve fetal lung maturation before delivery. Each exposed pregnancy was matched with one that did not receive antenatal corticosteroids (ACS) (control), based on gestational age at delivery and birth weight. The primary adverse outcome was a composite of abnormal condition at birth, major neonatal morbidity or perinatal death.Results A total of 86 pregnancies that received ACS were matched to 86 controls. The two groups were similar with respect to gestational age (33.1 vs 33.3 weeks), EFW (1673 vs 1634 g) and UCR (0.68 vs 0.62) at inclusion, and gestational age at delivery (35.5 vs 35.9 weeks) and birth weight (1925 vs 1948 g). No significant differences were observed between the exposed and non-exposed groups in the incidence of composite adverse outcome (28% vs 24%; P = 0.73) or any of its elements.Conclusion The present data do not show a beneficial effect of steroids on short-term outcome of fetuses with late FGR.

The placenta is a central structure in pregnancy and has pleiotropic functions. This organ grows incredibly rapidly during this period, acting as a mastermind behind different fetal and maternal processes. The relevance of the placenta extends far beyond the pregnancy, being crucial for fetal programming before birth. Having integrative knowledge of this maternofetal structure helps significantly in understanding the development of pregnancy either in a proper or pathophysiological context. Thus, the aim of this review is to summarize the main features of the placenta, with a special focus on its early development, cytoarchitecture, immunology, and functions in non-pathological conditions. In contraposition, the role of the placenta is examined in preeclampsia, a worrisome hypertensive disorder of pregnancy, in order to describe the pathophysiological implications of the placenta in this disease. Likewise, dysfunction of the placenta in fetal growth restriction, a major consequence of preeclampsia, is also discussed, emphasizing the potential clinical strategies derived. Finally, the emerging role of the placenta in maternal chronic venous disease either as a causative agent or as a consequence of the disease is equally treated., Unión Europea, Comunidad de Madrid, Instituto de Salud Carlos III, Halekulani S.L., Depto. de Salud Pública y Materno - Infantil, Fac. de Medicina, TRUE, pub

Introduction: Fetal growth restriction (FGR) is a clinical condition wherein a fetus fails to achieve the expected growth potential. Although FGR is the leading cause of perinatal morbidity and mortality, there is a lack of knowledge about the long-term developmental outcomes of children who had FGR in Japan. Here, we sought to clarify the features of neurodevelopmental outcomes in preterm-born children with severe FGR (sFGR) and identify associated clinical factors. Methods: The clinical data of 26 preterm sFGR cases and 26 preterm appropriate for gestational age (AGA) cases with a similar gestational age distribution were reviewed retrospectively. Developmental quotient (DQ) scores assessed during the 1- and 2-year corrected ages using the Kyoto Scale of Psychological Development were analyzed. Results: sFGR was diagnosed at 26 (18-34) weeks of gestation, and the gestational age at delivery was 31 (25-36) weeks. The overall DQ scores of children in the sFGR group were significantly lower than those in the AGA group (80 vs. 90.5, P = 0.0127). Of the three areas that comprise the DQ (Postural-Motor, Cognitive-Adaptive, and Language-Social), the sFGR group only showed significantly lower DQ scores (72.5 vs. 88, P = 0.0255) in the Language-Social area. Both fetal body weight and fetal body weight Z score at birth significantly correlated with the DQ scores (r = 0.4912, P = 0.0108, and r = 0.5621, P = 0.0028), whereas neither the duration of fetal growth arrest nor the gestational age at birth correlated with the DQ scores (r = 0.3598, P = 0.0842, and r = 0.3522, P = 0.0776). Conclusions: Our results indicate that preterm-born children with sFGR have greater neurodevelopmental impairment than preterm-born children without FGR, specifically in terms of the DQ scores for the Language-Social area. It is imperative to encourage continuous long-term follow-up and appropriate interventions after birth.

Objectives: To determine the trajectories of platelet counts and the prevalence of gestational thrombocytopenia (<150 × 10^9/L) during normal pregnancies and pregnancies with complications, such as hypertensive disorders of pregnancy (HDP), preeclampsia, and fetal growth restriction (FGR). Study design: A multicenter retrospective study was conducted using laboratory data on women who delivered term singletons at 11 primary maternity care units between 2011 and 2018 (n = 35,045), and non-pregnant women who underwent a medical check-up between 2016 and 2019 (n = 61,189). After 1:1 matching, 28,073 pregnant women and 28,073 non-pregnant women were selected for analysis. Main outcomes measures: The trajectories of platelet counts and prevalence of gestational thrombocytopenia were evaluated in normal pregnant women, pregnant women with complications, and non-pregnant women. Results: The platelet counts declined throughout pregnancy, with the nadir occurring on postpartum day 1. The platelet counts recovered to the level of the non-pregnant state at postpartum 2–7 days. The mean platelet counts at postpartum day 1 decreased by an estimated 19.8% and 9.7% compared to those in the non-pregnant state and first trimester, respectively. The prevalence of gestational thrombocytopenia in normal pregnant women at 37–41 gestational weeks and in pregnant women with complications of HDP, preeclampsia, and FGR were 6.1%, 7.3%, 17.5%, and 7.7%, respectively. Conclusion: Platelet counts declined throughout pregnancy and recovered to the level of the non-pregnant state in the early postpartum period. Gestational thrombocytopenia is common during normal pregnancy, and its prevalence is significantly higher in women with preeclampsia.

Fetal growth restriction (FGR) is a major obstetric problem affecting 3–9% of pregnancies. It is associated with increased perinatal mortality and morbidity as well as increased risk for adverse long-term outcome. The mechanisms leading to neurodevelopmental and cardiovascular problems later in life in FGR are still widely unknown. The present study evaluated the impact of fetal growth and fetal circulatory changes typical of placental insufficiency on long-term outcome at early school age. Neurologic evaluations included parental questionnaires, clinical examinations, language and communication skill assessments and magnetic resonance imaging (MRI) of the head, including detailed diffusion tensor imaging of the white matter. Cardiovascular health was assessed by examining heart rate variability and blood pressure. The findings in children born with FGR were compared to the findings of their gestational age-matched appropriately grown peers (AGA). Furthermore, the impact of prenatal fetoplacental hemodynamic findings on long-term outcomes was studied. Clinical evaluations revealed that children born with FGR, who showed abnormal umbilical artery blood flow, fetal venous circulatory changes and abnormal cardiac function prenatally at any gestational age, were at increased risk for poor neurocognitive development at early school age. Furthermore, significant placental insufficiency and blood flow redistribution increased the risk of poor literacy and communication skills compared with children with normal fetal growth. According to MRI scans, children born with FGR had smaller intracranial volumes at early school age than their AGA peers, with no difference in grey and white matter volumes. In addition, they showed changes in white matter microstructure in several areas when compared with AGA children, indicating that poor fetal growth impacts white matter maturation. In the evaluation of cardiovascular health at early school age, children born with FGR and p, Tiivistelmä Sikiöaikaista kasvuhidastumaa esiintyy 3–9 % raskauksista. Sikiöaikaiseen kasvuhidastumaan liittyy lisääntynyt riski syntymänjälkeiseen sairastavuuteen ja kuolleisuuteen sekä kohonnut riski myöhemmän neurokognitiivisen kehityksen ongelmiin sekä sydän- ja verisuonisairauksiin. Biologisia tekijöitä, jotka liittyvät pitkäaikaisiin neurologisiin ja sydän- ja verisuonisairauksiin, tunnetaan huonosti. Tässä tutkimuksessa tarkasteltiin sikiöaikaisen kasvuhidastuman ja istukan vajaatoiminnalle ominaisten verenkierron muutosten vaikutusta lasten neurologiseen kehitykseen sekä sydän- ja verenkiertoelimistön terveyteen varhaisessa kouluiässä. Neurologista kehitystä arvioitiin kliinisten tutkimusten, kyselylomakkeiden, puheterapeutin tutkimuksen sekä pään magneettitutkimuksen (MRI) avulla. Lisäksi selvitimme, ovatko sikiöaikaiset verenkierron muutokset yhteydessä sydämen sykevariaation tai verenpaineen poikkeavuuksiin sikiöaikaisesta kasvuhidastumasta kärsineillä lapsilla. 8–10-vuotiaiden sikiöaikaisesta kasvunhidastumasta kärsineiden lasten löydöksiä verrattiin raskauden keston suhteen kaltaistettuihin verrokkeihin, joiden sikiöaikainen kasvu oli normaalia. Tämän tutkimuksen mukaan sikiöaikaiset muutokset napavaltimon ja laskimopuolen verenkierrossa sekä sydämen toiminnassa ovat raskauden kestosta riippumattomia riskitekijöitä neurokognitiivisen kehityksen ongelmille varhaisessa kouluiässä. Lisäksi havaitsimme, että poikkeava napavaltimon verenvirtaus ja verenkierron uudelleenjakautuminen ovat yhteydessä kielellisen kehityksen ongelmiin. MRI-tutkimusten mukaan kasvunhidastumasta kärsineillä lapsilla aivojen kokonaistilavauus oli pienempi kuin verrokeilla varhaisessa kouluiässä, vaikka muutoksia harmaan tai valkean aineen tilavuuksissa ei todettu. Lisäksi sikiöaikaisesta kasvuhidastumasta kärsineillä lapsilla todettiin muutoksia aivojen valkean aineen rakenteessa, viitaten siihen, että sikiöaikaisen kasvun häiriintyminen vaikuttaa valkean aivoaineen kypsymiseen. Syd

Exposure to pregnancy complications, including preeclampsia (PE), has lifelong influences on offspring’s health. We have previously reported that experimental PE, induced in mice by administration of adenoviral sFlt1 at gestational day 8.5 combined with LPS at day 10.5, results in symmetrical growth restriction in female and asymmetrical growth restriction in male offspring. Here, we characterize the molecular phenotype of the fetal brain and liver with respect to gene transcription and DNA methylation at the end of gestation.In fetal brain and liver, expression and DNA methylation of several key regulatory genes is altered by PE exposure, mostly independent of fetal sex. These alterations point toward a decreased gluconeogenesis in the liver and stimulated neurogenesis in the brain, potentially affecting long-term brain and liver function. The observed sex-specific growth restriction pattern is not reflected in the molecular data, showing that PE, rather than tissue growth, drives the molecular phenotype of PE-exposed offspring.

Problem Pregnancy complications and adverse birth outcomes are in part fueled by the rise in obesity and its associated co-morbidities in western societies. Fetal healthy development and placental function are disturbed by an obese, inflammatory environment associated with cytokines, such as interleukin-6, causing inadequate supply of nutrients to the fetus and perinatal programming with severe health consequences. Method of study Mice received high fat diet (HFD) before and during gestation to induce obesity. We performed an IL-6 receptor antibody (MR16-1) treatment in pregnant obese mice at embryonic days E0.5, E7.5 and E14.5 to investigate whether this could ameliorate HFD-induced and obesity-associated placental dysfunction, evaluated by stereology and western blot, and improve offspring outcome at E15.5 in obese dams. Results We observed fewer fetuses below the 10th percentile and placental vascularization was less aggravated following MR16-1 treatment of obese dams, showing slight improvements in labyrinth zone (Lz) vascularization. However, placental dysfunction and fetal growth restriction were still apparent in MR16-1 dams compared to lean control dams. Molecular analysis showed significantly elevated IL-6 level in placentas of MR16-1 treated dams. Conclusion Treatment with MR16-1 blocks IL-6 signaling in the placenta, but has only limited effects on preventing HFD-associated placental dysfunction and offspring outcomes in mice, suggesting further mechanisms in the deterioration of placental vascularization and fetal nutrient supply as a consequence of maternal obesity.

Background: Chemotherapy crosses the placenta, however, it remains unclear to what extent it affects fetal growth. The current literature suggests up to 21% of the offspring of women receiving chemotherapy are small for gestational age (SGA, birth weight <10th percentile). Limiting research to birth weights only might misjudge fetal growth restriction (FGR) in this high-risk population with multiple risk factors for impaired fetal growth. Moreover, the role of the duration of chemotherapy and gestational age at initiation of chemotherapy in fetal growth is yet poorly understood. Objective: This retrospective cohort study evaluates fetal growth and neonatal birthweights in pregnant women receiving chemotherapy. Study design: All pregnant patients, registered by the International Network of Cancer, Infertility and Pregnancy (INCIP), treated with chemotherapy with at least two ultrasounds reporting on fetal growth, were eligible for this study. Duration and gestational age at initiation of chemotherapy were our major determinants, followed by cancer type and stage, maternal characteristics (parity, BMI, ethnicity hypertension, and diabetes) and individual cytotoxic agents (anthracycline, taxanes, and platinum). Fetal growth outcomes were described using the following mutually exclusive groups (1) FGR, based on a Delphi consensus (2016); (2) “low risk SGA” (birth weight below the 10th percentile), but an estimated growth above the 10th percentile; (3) “fetal growth disturbance”, which did not meet all FGR criteria; (4) “non-FGR”. Obstetric and oncological characteristics were compared between the growth impaired groups and non-FGR group. We calculated estimated fetal weight (EFW) according to Hadlock’s formula (1991) and birth weight percentile according to Nicolaides (2018). We used univariable and multivariable regression, and linear mixed effect models to investigate the effect of duration and gestational age at initiation of chemotherapy on birth weight, and feta

The aim was to assess the association between fetal growth restriction (FGR) and fetal heart rate variability (FHRV) in relation to fetal movements. A prospective observational cohort study was performed. Non-invasive fetal electrocardiography (NI-FECG) allowed beat-to-beat assessments with <5% corrections of RR intervals. FHRV analyses included: Root mean square of successive RR interval differences (RMSSD), high frequency power (HF power), and low frequency power (LF power). Fetal movements were categorized by continuous ultrasound scanning. We enrolled 36 singleton pregnant women expecting a small fetus (< the 2.3 percentile of mean weight for gestational age) diagnosed by ultrasound, of whom 25 presented with a birthweight < the 2.3 percentile. Among these, 11 were excluded due to low quality NI-FECG recordings, leaving 14 women with 28 recordings eligible for inclusion in the analyses. The control group consisted of 22 healthy fetuses with birthweights between the 10th and the 90th percentile (average for gestational age [AGA]). In FGR fetuses the HRV response to respiratory activity was comparable to that of AGA fetuses. RMSSD (Ratio 1.54 [95% CI: 1.33; 1.79]) and HF power (Ratio 2.88 [95% CI: 2.12; 3.91]) increased, whereas LF/HF power (Ratio: 0.44 [95% CI: 0.31;0.63]) decreased. However, during fetal quiescence, FGR fetuses differed significantly from AGA fetuses. Compared to AGA fetuses, FGR fetuses displayed lower RMSSD (Ratio 0.77 (95% CI: 0.58; 1.02)) and HF power (Ratio 0.56 (95% CI:0.32; 0.98)). This reduction was associated with the severity of the FGR. In conclusion, FGR fetuses displayed a respiratory sinus arrhythmia (RSA) comparable to AGA fetuses; however, more important, parameters representing cardiac vagal activity were impaired in FGR fetuses during quiescence. RSA may constitute an intrinsic function of the cardiovascular system, which is unaffected by fetal compromise. However, the basic cardiac outflow assessed during fetal qui

This thesis applied magnetic resonance imaging (MRI) to investigate to what extent very preterm birth due to early onset fetal growth restriction (FGR) impacts the cardiovascular system and kidneys in adolescence. The thesis further investigated whether FGR exacerbates the organ-specific effects of very preterm birth.Study I validated a widely available non-contrast enhanced MRI method for quantification of renal cortical and medullary parenchymal volumes and showed that kidney volumes can be quantified with high accuracy and precision.Study II validated an MRI method for pulse wave velocity (PWV) acquisition in neonates and adolescents and showed how the acquired PWV was influenced by commonly used MRI methods. The study proposed the use of 3D angiography images and the time-to-foot method for accurate and precise PWV acquisition.Study III implemented the proposed PWV method from Study II and 24-hour ambulatory blood pressure measurements and showed that very preterm birth due to early onset FGR was associated with higher, yet normal, blood pressure in adolescent boys while very preterm birth was associated with higher arterial stiffness in girls.Study IV showed that very preterm birth was associated with smaller ventricular volumes without alterations in left or right longitudinal and radial pumping. Early onset FGR did not exacerbate the effects of very preterm birth.Study V implemented the newly validated non-contrast enhanced MRI method from Study I together with biomarkers of kidney function. Very preterm birth due to FGR was associated with smaller total kidney and medullary kidneyvolumes, but not with markers of kidney dysfunction or renin-angiontensin-aldosterone system activation in adolescence.This thesis concludes that adolescents born very preterm with and without preceding fetal growth restriction show alterations in cardiovascular and renal morphology. Changes were more pronounced in girls. Cardiovascular andkidney function were however normal, possib

Background: Intrauterine growth restriction is associated with an increased risk of cardiovascular changes neonatally. However, the underlying pathways are poorly understood, and it is not clear whether the dysfunction is already present in the fetus. Objective: This study aimed to investigate fetal cardiac dimensions assessed from images at the second trimester anatomy scan from fetuses classified postnatally as small for gestational age and intrauterine growth restricted and compare them with appropriate for gestational age fetuses. Study Design: This was a substudy from The Copenhagen Baby Heart Study, a prospective, multicenter cohort study including fetuses from the second trimester of pregnancy in Copenhagen from April 2016 to October 2018. The mothers were recruited at the second trimester anatomy scan that included extended cardiovascular image documentation followed by consecutively measured heart biometry by 2 investigators blinded for the pregnancy outcome. The fetuses were classified postnatally as small for gestational age and intrauterine growth restricted according to the International Society of Ultrasound in Obstetrics and Gynecology 2020 guidelines using birthweight and with a retrospective assessment of Doppler flow. The mean differences in the cardiovascular biometry were adjusted for gestational age at the time of the second trimester scan and the abdominal circumference. The z-scores were calculated, and the comparisons were Bonferroni corrected (significance level of P<.005). Receiver operating characteristic curves were computed after performing backward regression on several maternal characteristics and biomarkers. Results: We included 8278 fetuses, with 625 (7.6%) of them being small for gestational age and 289 (3.5%) being intrauterine growth restricted. Both small for gestational age and intrauterine growth restricted fetuses had smaller heart biometry, including the diameter at the location of the aortic valve (P<.005), the asce

Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development., Spanish Ministry of Science and Innovation, Fac. de Veterinaria, TRUE, pub

Uvod: Dat je uvid u trudnoću kao hiperkoagulatno stanje i fiziološke efekte uteroplacentne konekcije, neophodne za uspešan razvoj trudnoće. Pregled literaturnih podataka dosadašnjih istraživanja dokazuje da neadekvatna placentna perfuzija u stanjima koja prevazilaze fiziološki nivo koagulabilnosti, dovodi do formiranja mikrotromboza uteroplacente jedinice. Vaskulopatija, kao bazični uzročnik pogoršanja uteroplacentne i fetoplacentne cirkulacije, dovodi do kompikacija trudnoće. Preventivnim dijagnostičkim i terapijskim procedurama, smanjujemo morbiditet majke, kao i morbiditet i mortalitet fetusa (rani gubici trudnoće, ponovljeni gubitak trudnoće prvog trimestra, gubitak trudnoće drugog i trećeg trimestra, preeklampsija, abrupcija placente, prevremeni porođaj, intrauterina smrt ploda, restrikcija fetalnog rasta, venski tromboembolizam). Klinička i bazična medicinska istraživanja dovode u vezu nasledne trombofilije i negativan ishod trudnoće. Data je analiza studija koja porede komplikacije trudnoće i hereditarne trombofilije, opis hereditarnih trombofilija, podela i klasifikacija. Nedostatak jake i konzistentne baze dokaza za kliničke smernice je doveo do različitih preporuka kliničarima. U odnosu na tromboprofilaksu, preporuke American College of Chest Physicians (ACCP), u poređenju sa preporukama Royal College of Obstetricians and Gynecologists (RCOG), nemaju apsolutni konsenzus. Za žene sa trombofilijama i istorijom negativnih ishoda trudnoće ovo je veoma delikatno i emotivno područje. Zato su klinički lekari u obavezi da aktivno kontrolišu poznate faktore rizika, i pored nedostatka kvalitetnih dokaza koji ovo podržavaju. Metod: Studija je sprovedena u Klinici za ginekologiju i akušerstvo Kliničkog centra Srbije u Beogradu retrospektivno (dve godine) i prospektivno (godinu dana). Ispitivanjem su obuhvaćene sve hospitalizovane trudnice u periodu od januara 2016. do decembra 2018. godine, kod kojih je utvrđena kongenitalna trombofilija. Studija je rađena delom retro, Introduction: The insight of pregnancy as hypercoagulable state and physilogical effects of uteroplacental connections that are both necessary for successful development of pregnancy. Literature data review of recent investigations proves that inadequate placental perfusion leads to the development of microthrombosis within the uteroplacental unit. Vasculopathy,as the main cause of worsening of the uteroplacental and fetoplacental circulation, leads to the complications of pregnancy. By preventive diagnostical and therapeutical procedures, we lower the morbidity and mortality of mothers, as well as the morbidity and mortality of fetus (early pregnancy losses, recurrent pregnancy loss, placental abruption, preterm delivery, interauterine fetal death, fetal growth restriction, venous thromboembolism). Clinical and basical medical researches suggest the connection between inherited thrombophilias and adverse pregnancy outcomes. The analysis of studies that compare complications of pregnancy and inherited thrombophilias, description of hereditary thrombophilias and their clasification is given. Missing the strong and consistant data base for clinical use has lead to different guidelines for clinical practice. Considering thromboprophylaxis, American College of Chest Physicians (ACCP) and Royal College of Obstetricians and Gynecologists (RCOG) do not have absolute consensus. For women with thrombophilias and positive personal history for adverse pregnancy outcomes, this is very delicate and emotional field. Because of that clinical doctors are obliged to actively control the risk factors, even though that the qualitive proofs that support this are missing. Methods: The study is undertaken in the Clinic for Gynecology and Obstetrics, Clinical Centre of Serbia retrospectively (for two years) and prospectively (for a year). We have encompassed all hospitalised pregnant women wih hereditary thromobophilia in the period from january 2016 till december 2018. The study has been

This study investigated whether primary school-aged children born with fetal growth restriction (FGR) are at greater risk for poor communication, narrative skills, and reading and spelling skills than children born with appropriate for gestational age (AGA) growth. The participants belonged to a prospectively collected FGR cohort born in 1998−2001 at the Oulu University Hospital, Oulu, Finland. The mothers with placental insufficiency were recruited from the high-risk prenatal unit of the Oulu University Hospital, Oulu, Finland. This cohort of 73 FGR fetuses was followed-up prenatally until the deliveries at 24−40 gestational weeks. Gestational age was confirmed in all cases with ultrasound before 20 gestational weeks. Fetal growth restriction was defined as birth weight below the 10th percentile and/or significant placental insufficiency (umbilical artery pulsatility index > 2SD for gestational age). Neonates with chromosomal and structural anomalies were excluded. 36 AGA children (birth weight ≥ 10th percentile for gestational age) were selected for the control group and matched with gestational age and delivery within ± 2 weeks of the index FGR neonate. Children born with FGR had more difficulties with all the studied language-based skills than their gestational age and age-matched AGA peers. Children born with FGR were more likely to have problems in communication skills than their AGA peers. The general communication skills according to the CCC-2 questionnaire, which embodies communication skills as a whole and gives a profile on the weaknesses and strengths of a child’s communication, were poorer for the FGR group than the AGA group. Children in the FGR group produced less informative and shorter narratives with simpler utterances than the children in the AGA group. Significantly more children in the FGR group performed below the 10th percentile normal values in word reading skills than children in the AGA group. 9- to 10-year-old third graders in the, Tiivistelmä Tutkimuksessa tarkasteltiin, eroaako lasten, joilla on todettu sikiöaikainen kasvunhidastuma (FGR, fetal growth restriction), kommunikoinnin, kerronnan ja lukemisen sekä kirjoittamisen taidot normaalisti kohdussa kasvaneiden lasten vastaavista taidoista alakouluiässä. Tutkimuslapset kuuluivat vuosien 1998─2001 aikana syntyneeseen Oulun yliopistollisen sairaalaan syntymäkohorttiin. Tutkimukseen kutsuttiin äidit, joilla todettiin istukan vajaatoiminta. Kasvultaan hidastuneiden sikiöiden (N=73) tilaa seurattiin 24–40 raskausviikoilla tapahtuneisiin synnytyksiin saakka. Raskauden kesto vahvistettiin ultraäänitutkimuksilla ennen 20. raskausviikkoa. Sikiöaikaisen kasvunhidastuman kriteerinä oli alle 10 persentiilin syntymäpaino raskauden kestoon suhteutettuna ja/tai merkittävä istukan toimintahäiriö (napavaltimon pulsatiliteetti-indeksi > 2SD raskauden kestoon suhteutettuna). Kaikki lapset, joilla todettiin kromosomi- ja/tai rakennepoikkeavuuksia suljettiin pois tutkimuksesta. Kohortin lapset kutsuttiin seurantatutkimukseen. Tutkimukseen osallistui 42 lasta, jotka tutkittiin vuosien 2007─2011 aikana Oulun yliopistollisessa sairaalassa (OYS) heidän ollessaan 8─10-vuotiaita. Kontrolliryhmänä toimivat saman ikäiset, raskauden keston ja syntymäajankohdan (±2 raskausviikkoa) suhteen kaltaistetut normaalipainoisina (syntymäpaino ≥ 10 persentiiliä suhteutettuna raskauden kestoon) syntyneet lapset (N=31). Lapsilta tutkittiin kommunikointitaidot vanhempien täyttämällä kyselyllä. Lisäksi arvioitiin kerronnan taidot sekä lukemisen ja kirjoittamisen taidot. Tuloksista kävi ilmi, että lapsilla, joilla oli todettu sikiöaikainen kasvunhidastuma, oli enemmän vaikeuksia kaikissa tutkituissa, kieleen perustuvissa taidoissa verrattuna normaalisti kasvaneiden kontrollilasten taitoihin. Arjen kommunikointitilanteet olivat heille haastavampia eivätkä mahdolliset vahvuudet riittäneet kompensoimaan kommunikoinnin eri osa-alueilla ilmeneviä haasteita. Lapset, joilla oli todettu sikiöa

ObjectiveWe hypothesized that infants with fetal growth restrictions have increased mortality and morbidity after congenital heart disease surgery.MethodsThe study included patients in The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010-2016) who underwent cardiac surgery at a corrected gestational age of ≤44 weeks. Patients were classified as severely (birth weight Z-score -4 to -2), moderately (Z-score -2 to -1), and mildly growth restricted (Z-score -1.0 to -0.5) and compared with a reference population (Z-score 0-0.5). Multivariable logistic regression clustering on center was used to evaluate the association of birth weight Z-score with operative mortality and postoperative complications and its interaction with gestational age was assessed.ResultsIn 25,244 patients, operative mortality was 8.6% and major complications occurred in 19.4%. Compared with the reference group, the adjusted odds ratio (AOR) of mortality was increased in infants with severe (AOR, 2.4; 95% confidence interval [CI], 2.0-3.0), moderate (AOR, 1.7; 95% CI, 1.4-2.0), and mild growth restriction (AOR, 1.4; 95% CI, 1.2-1.6). The AOR for major postoperative complications was increased for severe (AOR, 1.4; 95% CI, 1.2-1.7) and moderate growth restriction (AOR, 1.2; 95% CI, 1.1-1.4). There was significant interaction between birth weight Z-score and gestational age (P = .007).ConclusionsEven birth weight Z-scores slightly below average are independent risk factors for mortality and morbidity in infants who undergo cardiac surgery. The strongest association between poor fetal growth and operative mortality exists in early-term infants. These novel findings might account for some of the previously unexplained variation in cardiac surgical outcomes.

BACKGROUND: Worldwide, hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR) and preterm birth remain the leading causes of maternal and fetal pregnancy-related mortality and (long-term) morbidity. Fetal cardiac deformation changes can be the first sign of placental dysfunction, which is associated with HDP, FGR and preterm birth. In addition, preterm birth is likely associated with changes in electrical activity across the uterine muscle. Therefore, fetal cardiac function and uterine activity can be used for the early detection of these complications in pregnancy. Fetal cardiac function and uterine activity can be assessed by two-dimensional speckle-tracking echocardiography (2D-STE), non-invasive fetal electrocardiography (NI-fECG), and electrohysterography (EHG). This study aims to generate reference values for 2D-STE, NI-fECG and EHG parameters during the second trimester of pregnancy and to investigate the diagnostic potential of these parameters in the early detection of HDP, FGR and preterm birth.METHODS: In this longitudinal prospective cohort study, eligible women will be recruited from a tertiary care hospital and a primary midwifery practice. In total, 594 initially healthy pregnant women with an uncomplicated singleton pregnancy will be included. Recordings of NI-fECG and EHG will be made weekly from 22 until 28 weeks of gestation and 2D-STE measurements will be performed 4-weekly at 16, 20, 24 and 28 weeks gestational age. Retrospectively, pregnancies complicated with pregnancy-related diseases will be excluded from the cohort. Reference values for 2D-STE, NI-fECG and EHG parameters will be assessed in uncomplicated pregnancies. After, 2D-STE, NI-fCG and EHG parameters measured during gestation in complicated pregnancies will be compared with these reference values.DISCUSSION: This will be the a large prospective study investigating new technologies that could potentially have a high impact on antepartum fetal monito

Worldwide, fetal growth restriction (FGR) affects 7 to 10% of pregnancies, or roughly 20.5 million infants each year. FGR not only increases neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR "programs" an obese phenotype are not well understood. Of note, studies demonstrate that FGR females are more prone to obesity as compared to males; however, the molecular mechanisms that lead to FGR are not known. Thus, I hypothesized that FGR causes sexually dimorphic programming of adipocytes by differentially regulating preadipocyte gene pathways. To test the hypothesis, we induced FGR using a sheep model subject to increased ambient hyperthermia. We collected perirenal adipose tissue from male and female near-term FGR and normal weight fetal lambs (N=4 in each group, 16 total). Second-generation RNA sequencing (RNAseq) was conducted on RNA isolated from adipose tissue to examine the differences in gene networks and pathways. For phenotypic results, averages across the four samples for each group were obtained. The current studies demonstrated that male FGR (MFGR) has a significantly greater mean fat globule area than normal-weight male fetus and a greater fat globule area than all other groups. In contrast, there was no significant difference in average fat globule area between female FGR (FFGR) and normal-weight female fetus. A four-way RNAseq comparison demonstrated significant differences in gene expression between FGR and control groups and between sexes. In conclusion, we observed a sexually dimorphic phenotype and gene pathways in response to FGR.

Preeclampsia and fetal growth restriction are among the most serious obstetric conditions worldwide. Though they affect so many, we still do not completely understand their pathogenesis, nor have good ways to detect or treat them. In this thesis, I aimed to: improve our understanding of placental and vascular adaptations in preeclampsia and growth restriction, assess the ability of candidate therapeutics to mediate vascular dysfunction associated with preeclampsia, and to explore new models of preeclampsia and the long-term impacts on maternal cardiovascular health. DAAM2 and NR4A2 transcripts are elevated in the circulation of individuals whose pregnancies are complicated by fetal growth restriction (with or without preeclampsia). In Chapters 2 and 3 of this thesis, I identified these transcripts are expressed in the placenta, but their expression in either growth restricted or preeclamptic placenta does not mirror the increased expression of DAAM2 and NR4A2 in the maternal circulation. Thus, they are unlikely to originate from the dysfunctional placenta. However, their expression in the placenta throughout gestation, and clear regulation under hypoxia suggest they have roles in normal placental development and placental dysfunction. LOX-1 is elevated in the maternal vasculature in preeclampsia. In contrast to this, I identified in Chapter 4 that LOX-1 expression is reduced in the preeclamptic placenta. Furthermore, its expression is reduced in trophoblast under hypoxia. Treatment of trophoblasts with candidate preeclampsia therapeutics, esomeprazole and lansoprazole, (proton pump inhibitors) increased LOX-1 expression. These findings suggest that LOX-1 has a distinct role in the placenta compared to the vasculature. In Chapters 5 and 6, I assessed the ability of statins and new generation antiplatelets to mitigate preeclampsia-associated vascular dysfunction. In a model of endothelial dysfunction, pravastatin and simvastatin reduced secretion of vasoconstrictor, e

BACKGROUND: The placenta is the functional interface between the mother and the fetus during pregnancy, and a critical determinant of fetal growth and life-long health. In the first trimester, it develops under a low-oxygen environment, which is essential for the conceptus who has little defense against reactive oxygen species produced during oxidative metabolism. However, failure of invasive trophoblasts to sufficiently remodel uterine arteries toward dilated vessels by the end of the first trimester can lead to reduced/intermittent blood flow, persistent hypoxia and oxidative stress in the placenta with consequences for fetal growth. Fetal growth restriction (FGR) is observed in ∼10% of pregnancies and is frequently seen in association with other pregnancy complications, such as preeclampsia (PE). FGR is one of the main challenges for obstetricians and pediatricians, as smaller fetuses have greater perinatal risks of morbidity and mortality and postnatal risks of neurodevelopmental and cardio-metabolic disorders. OBJECTIVE AND RATIONALE: The aim of this review was to examine the importance of placental responses to changing oxygen environments during abnormal pregnancy in terms of cellular, molecular and functional changes in order to highlight new therapeutic pathways, and to pinpoint approaches aimed at enhancing oxygen supply and/or mitigating oxidative stress in the placenta as a mean of optimizing fetal growth. SEARCH METHODS: An extensive online search of peer-reviewed articles using PubMed was performed with combinations of search terms including pregnancy, placenta, trophoblast, oxygen, hypoxia, high altitude, FGR and PE (last updated in May 2020). OUTCOMES: Trophoblast differentiation and placental establishment are governed by oxygen availability/hypoxia in early pregnancy. The placental response to late gestational hypoxia includes changes in syncytialization, mitochondrial functions, endoplasmic reticulum stress, hormone production, nutrient handling a

Growing evidence indicates that reduced uterine perfusion pressure (RUPP) triggers the cascade of events leading to preeclampsia. Edaravone is a powerful free radical scavenger used for the treatment of ischemia/reperfusion diseases due to its anti-oxidative stress and anti-inflammatory properties. Here we investigate the effect of edaravone (3 mg/kg) on different maternal and fetal outcomes of RUPP-induced placental ischemia mice model. RUPP surgery was performed on gestation day (GD) 13 followed by edaravone injection from GD14 to GD18, sacrifice day. The results showed that edaravone injection significantly decreased the maternal blood pressure (113.2 +/- 2.3 mmHg) compared with RUPP group (131.5 +/- 1.9 mmHg). Edaravone increased fetal survival rate (75.4%) compared with RUPP group (54.4%), increased fetal length, weights, and feto-placental ratio (7.2 and 5.7 for RUPP and RUPP-Edaravone groups, respectively) compared with RUPP group. In addition, RUPP resulted in many fetal morphological abnormalities as well as severe delayed ossification, however edaravone decreased the morphological abnormalities and increased the ossification of the fetal endoskeleton. Edaravone improved the histopathological structure of the maternal kidney and heart as well as decreased the elevated blood urea and creatinine levels (31.5 +/- 0.15 mg/dl (RUPP), 25.6 +/- 0.1 mg/dl (RUPP+edaravone) for urea and 5.4 +/- 0.1 mg/dl (RUPP), 3.5 +/- 0.1 mg/dl (RUPP+edaravone) for creatinine) and decreased cleaved caspase-3 expression in the maternal kidney. In conclusion, this study demonstrated that our RUPP mice model recapitulated preeclampsia symptoms and edaravone injection ameliorated most of these abnormalities suggesting its effectiveness and potential application in preeclampsia treatment regimes.

ObjectiveOur objective was to test the association of fetal adrenal size with perinatal morbidity among fetuses with fetal growth restriction (FGR; estimated fetal weight [EFW] < 10th percentile).Study designThis was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) adrenal study, which measured fetal adrenal gland size at 22 to 30 weeks' gestation. We analyzed the transverse adrenal area (TAA) and fetal zone area (absolute measurements and corrected for fetal size) and the ratio of the fetal zone area to the total transverse area using a composite perinatal outcome of stillbirth, neonatal intensive care unit admission, respiratory distress syndrome, necrotizing enterocolitis, retinopathy of prematurity, sepsis, mechanical ventilation, seizure, or death. Among fetuses with FGR, adrenal measurements were compared between those that did and did not experience the composite perinatal outcome.ResultsThere were 1,709 eligible neonates. Seven percent (n = 120) were diagnosed with FGR at the time of adrenal measurement, and 14.7% (n = 251) experienced perinatal morbidity. EFW-corrected and absolute adrenal measurements were similar among fetuses with and without FGR as well as among those who did and did not experience morbidity. The area under the curve for corrected TAA was 0.52 (95% confidence interval 0.38-0.67).ConclusionIn our cohort, adrenal size was not associated with risk of morbidity among fetuses with FGR.