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Objective: To assess the maternal blood levels of fatty acids (FAs) in pregnancies with fetal growth restriction (FGR). Methods: This prospective cross-sectional study included pregnant women with gestational age between 26 and 37 + 6 weeks with FGR and appropriate for gestational age (AGA) fetuses. The levels of saturated, trans, monounsaturated, and polyunsaturated FAs were measured using centrifugation and liquid chromatography. The Student’s t-test, Mann-Whitney test, and general linear model, with gestational age and maternal weight as covariants, were used to compare FA levels and the FGR and AGA groups. The Chi-square was used to evaluate the association between groups and studied variables. Results: Maternal blood sample was collected from 64 pregnant women, being 24 FGR and 40 AGA. A weak positive correlation was found between the palmitoleic acid level and maternal weight (r = 0.285, p = 0.036). A weak negative correlation was found between the gamma-linoleic acid level and gestational age (r = −0.277, p = 0.026). The median of the elaidic acid level (2.3 vs. 4.7ng/ml, p = 0.045) and gamma-linoleic acid (6.3 vs. 6.6ng/ml, p = 0.024) was significantly lower in the FGR than the AGA group. The palmitoleic acid level was significantly higher in the FGR than AGA group (50.5 vs. 47.6ng/ml, p = 0.033). Conclusion: Pregnant women with FGR had lower elaidic acid and gamma-linoleic acid levels and higher palmitoleic acid levels than AGA fetuses. Resumo Objetivo: Avaliar os níveis sanguíneos maternos de ácidos graxos (AGs) em gestações com restrição de crescimento fetal (RCF). Métodos: Este estudo prospectivo transversal incluiu gestantes com idade gestacional entre 26 e 37 semanas e 6 dias com RCF e fetos adequados para a idade gestacional (AIG). Os níveis de ácidos graxos saturados, trans, monoinsaturados e poliinsaturados foram medidos usando centrifugação e cromatografia líquida. O teste t-Student, o teste de Mann-Whitney e o modelo linear geral, com idade gestacional e peso materno como covariantes, foram utilizados para comparar os níveis de AGs e os grupos RCF e AIG. O teste Qui-quadrado foi utilizado para avaliar a associação entre os grupos e as variáveis estudadas. Resultados: Amostra de sangue materno foi coletada de 64 gestantes, sendo 24 RCF e 40 AIG. Uma correlação positiva fraca foi encontrada entre o nível de ácido palmitoleico e o peso materno (r = 0,285, p = 0,036). Uma correlação negativa fraca foi encontrada entre o nível de ácido gama-linoleico ea idade gestacional (r = −0,277, p = 0,026). A mediana do nível de ácido elaídico (2,3 vs. 4,7 ng/ml, p = 0,045) e ácido gama-linoleico (6,3 vs. 6,6 ng/ml, p = 0,024) foram significativamente menores no grupo RCF do que no grupo AIG. O nível de ácido palmitoleico foi significativamente maior no grupo RCF do que no grupo AIG (50,5 vs. 47,6 ng/ml, p = 0,033). Conclusão: Gestantes com RCF apresentaram níveis mais baixos de ácido elaídico e ácido gama-linoleico e níveis mais elevados de ácido palmitoleico do que os fetos AIG.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists mostly of maternal mononuclear cells and fibrin depositions, which are both indicators for the severity of the intervillous infiltrate. The severity of the intervillous infiltrate as well as the clinical outcomes of pregnancy differ between cases. Our objective is to determine the relation between the severity of the intervillous infiltrate and the clinical outcomes of CHI.METHODS: Cases of CHI were semi-quantitatively graded based on histopathological severity scores. Hereto, CD68 positive mononuclear cells were quantified, fibrin depositions visualized by both a PTAH stain and an immuohistochemical staining, and placental dysfunction was assessed via thrombomodulin staining.RESULTS: This study included 36 women with CHI. A higher CD68 score was significantly associated with a lower birthweight. Loss of placental thrombomodulin was associated with lower gestational age, lower birthweight, and a lower placenta weight. The combined severity score based on CD68 and PTAH was significantly associated with fetal growth restriction, and the joint score of CD68 and fibrin was associated with birthweight and placental weight.DISCUSSION: More severe intervillous infiltrates in CHI placentas is associated with a lower birth weight and placental weight. Furthermore, this study proposes thrombomodulin as a possible new severity marker of placental damage. More research is needed to better understand the pathophysiology of CHI.

Contains fulltext : 291971.pdf (Publisher’s version ) (Open Access) BACKGROUND: Several human randomised controlled trials (RCTs) are investigating the effects of statins on pre-eclampsia (PE) and fetal growth restriction (FGR). This cross-species meta-analysis summarises the preclinical evidence of statin use for PE and FGR. OBJECTIVES: Evaluate the effects of statins on maternal blood pressure (MBP) and birthweight (BW) in pregnancies complicated by PE or FGR. SEARCH STRATEGY: PubMed and Embase.com were searched on 10 May 2022 using 'statins' and 'pregnancy'. SELECTION CRITERIA: We included RCTs and cohorts with matched control groups as well as animal studies. DATA COLLECTION AND ANALYSIS: The main outcomes were MBP in mmHg and BW in grams. The standardised mean difference (SMD) with a 95% confidence interval (CI) was calculated. Subgroup analyses on species, statin, dose, timing and route of administration were performed if subgroups included at least three studies. MAIN RESULTS: Our data included one human and 12 animal studies. Prenatal administration of statins significantly reduced MBP during pregnancy (SMD -2.49 mmHg [95% CI -4.26 to -0.71], p = 0.01). There was no significant effect of statins on BW (SMD 0.69 [95% CI -0.65 to 2.03], p = 0.28). Our subgroup analyses showed no effect on MBP of different doses, species or route of administration. CONCLUSIONS: Our cross-species meta-analyses demonstrate that statins only reduce maternal blood pressure in rodent pregnancies complicated by pre-eclampsia or fetal growth restriction and have no effect on birthweight across species. The broad confidence intervals, inconsistent direction of the observed effects across the studies and large risk of bias lead us to conclude that a solid base for further human RCTs is lacking.

Introduction: Transverse relaxation time (T2*) is related to tissue oxygenation and morphology. We aimed to describe T2* weighted MRI in selected fetal organs in normal pregnancies, and to investigate the correlation between fetal organ T2* and placental T2*, birthweight (BW) deviation, and redistribution of fetal blood flow. Methods: T2*-weighted MRI was performed in 126 singleton pregnancies between 23+6- and 41+3-weeks’ gestation. The T2* value was obtained from the placenta and fetal organs (brain, lungs, heart, liver, kidneys, and spleen). In normal BW pregnancies (BW > 10th centile), the correlation between the T2* value and gestational age (GA) at MRI was estimated by linear regression. The correlation between fetal organ Z-score and BW group was demonstrated by boxplots and investigated by analysis of variance (ANOVA) for each organ. Results: In normal BW pregnancies fetal organ T2* was negatively correlated with GA. We found a significant correlation between BW group and fetal organ T2* z-score in the fetal heart, kidney, lung and spleen. A positive linear correlation was demonstrated between fetal organ T2* and outcomes related to placental function such as BW deviation and placenta T2* in all investigated fetal organs except for the fetal liver. In the fetal heart, kidneys, and spleen the T2* value showed a significant correlation with fetal redistribution of blood flow (Middle cerebral artery Pulsatility Index) before delivery. Discussion: Fetal T2* is correlated with BW, placental function, and redistribution of fetal blood flow, suggesting that fetal organ T2* reflects fetal oxygenation and morphological changes related to placental dysfunction.

RESUMEN Objetivos: Determinar el desempeño predictivo de la definición de retardo de crecimiento fetal (RCF) de ultrasonografía de la Sociedad de Medicina Materno Fetal (SMMF), consenso Delphi (CD) y Medicina Fetal de Barcelona (MFB) respecto a resultados adversos perinatales en cada una, e identificar si hay asociación entre diagnóstico de RCF y resultados adversos perinatales. Materiales y métodos: Se realizó un estudio de cohorte retrospectiva. Se incluyeron gestantes con embarazo único de 24 a 36 semanas con 6 días, quienes fueron atendidas en la unidad de medicina materna fetal con evaluación ecográfica de crecimiento fetal y atención de parto en una institución hospitalaria pública de referencia ubicada en Popayán, Colombia. Se excluyeron embarazos con hallazgos ecográficos de anomalías congénitas. Muestreo por conveniencia. Se midieron variables sociodemográficas y clínicas de las gestantes al ingreso, la edad gestacional, el diagnóstico de RCF y el resultado adverso perinatal compuesto. Se analizó la capacidad predictiva de tres criterios diagnósticos de restricción de crecimiento fetal para malos resultados perinatales y la asociación entre el diagnóstico de RCF y mal resultado periantal. Resultados: Se incluyeron 228 gestantes, cuya edad media fue de 26,8 años, la prevalencia de RCF según los tres criterios fue de 3,95 %, 16,6 % y 21,9 % para CD, MFB y SMMF respectivamente. Ningún criterio aportó área bajo la curva aceptable para predicción de resultado neonatal adverso compuesto, el diagnóstico de RCF por CD y SMMF se asoció a resultados adversos perinatales con RR de 2,6 (IC 95 %: 1,54,3) y 1,57 (IC 95 %: 1,01-2,44), respectivamente. No se encontró asociación por MFB RR: 1,32 (IC 95 %: 0,8-2,1). Conclusiones: Ante un resultado positivo para RCF, el método Delphi se asocia de manera más importante a los resultados perinatales adversos. Los tres métodos tienen una muy alta proporción de falsos negativos en la predicción de mal resultado perinatal. Se requieren estudios prospectivos que reduzcan los sesgos de medición y datos ausentes. ABSTRACT Objectives: To determine the predictive performance of fetal growth restriction by Maternal Fetal Medicine Society (MFMS) definition of ultrasound, the Delphi consensus (DC) and the Barcelona Fetal Medicine (BFM) criteria for adverse perinatal outcomes, and to identify whether there is an association between the diagnosis of fetal growth restriction (FGR) and adverse perinatal outcomes. Material and methods: A retrospective cohort study was conducted including women with singleton pregnancies between 24 and 36 weeks of gestation seen at the maternal fetal medicine unit for ultrasound assessment of fetal growth and delivery care in a public referral hospital in Popayán, Colombia. Pregnancies with ultrasound findings of congenital abnormalities were excluded. Convenience sampling was used. Sociodemographic and clinical variables were measured on admission; additional variables were gestational age, FGR diagnosis and adverse composite perinatal outcome. The predictive ability of three fetal growth restriction diagnostic criteria for poor perinatal outcomes was analyzed and asociation between FGR and adverse perinatlal outcomes. Results: Overall, 228 pregnant women with a mean age of 26.8 years were included; FGR prevalence according to the three criteria was 3.95 %, 16.6 % and 21.9 % for DC, BFM and MFMS, respectively. None of the criteria resulted in an acceptable area under the curve for the prediction of the composite adverse neonatal outcome; FGR diagnosis by DC and MFMS were associated with adverse perinatal outcomes with a RR of 2.6 (95 % CI: 1.5-4.3) and 1.57 (95 % CI: 1.01-2.44) respectively. No association was found for BFM RR: 1.32 (95 % CI: 0.8-2.1). Conclusions: Given a positive result for FGR, the Delphi method is significantly associated with adverse perinatal outcomes. The proportion of false negative results for a poor perinatal outcome is high for the three methods. Prospective studies that reduce measurement and attrition bias are required.

Background: Preeclampsia and fetal growth restriction increase cardiopulmonary disease risk for affected offspring and occur more frequently at high-altitude (≥2500 m). Retrospective studies indicate that birth to a preeclampsia woman at high altitude increases the risk of pulmonary hypertension (PH) in later life. This prospective study asked whether preeclampsia with or without fetal growth restriction exaggerated fetal hypoxia and impaired angiogenesis in the fetal lung, leading to neonatal cardiopulmonary circulation abnormalities and neonatal or infantile PH. Methods and Results: We studied 79 maternal-infant pairs (39 preeclampsia, 40 controls) in Bolivia (3600–4100 m). Cord blood erythropoietin, hemoglobin, and umbilical artery and venous blood gases were measured as indices of fetal hypoxia. Maternal and cord plasma levels of angiogenic (VEGF [vascular endothelial growth factor]) and antiangiogenic (sFlt1 [soluble fms-like tyrosine kinase]) factors were determined. Postnatal echocardiography (1 week and 6–9 months) assessed pulmonary hemodynamics and PH. Preeclampsia augmented fetal hypoxia and increased the risk of PH in the neonate but not later in infancy. Pulmonary abnormalities were confined to preeclampsia cases with fetal growth restriction. Maternal and fetal plasma sFlt1 levels were higher in preeclampsia than controls and positively associated with PH. Conclusions: The effect of preeclampsia with fetal growth restriction to increase fetal hypoxia and sFlt1 levels may impede normal development of the pulmonary circulation at high altitude, leading to adverse neonatal pulmonary vascular outcomes. Our observations highlight important temporal windows for the prevention of pulmonary vascular disease among babies born to highland residents or those with exaggerated hypoxia in utero or newborn life.

OBJECTIVE: To explore the pattern of fetal cortical development in pregnancies complicated by pre-eclampsia (PE), with and without a small-for-gestational-age (SGA) fetus, compared to uncomplicated pregnancies. METHODS: This was a prospective observational study including singleton pregnancies complicated by normotensive SGA (birth weight < 10(th) centile) (n = 77), PE with an appropriate-for-gestational-age (AGA) fetus (n = 76) or PE with a SGA fetus (n = 67), and 128 uncomplicated pregnancies (normotensive AGA) matched by gestational age at ultrasound. All pregnancies underwent detailed neurosonography, using a transabdominal and transvaginal approach, at 31-35 weeks' gestation to assess the depth of the insula, Sylvian fissure, parieto-occipital sulcus, cingulate sulcus and calcarine sulcus. All measurements were adjusted for biparietal diameter (BPD). In addition, a grading score of cortical development was assigned to each brain structure, ranging from Grade 0 (no development) to Grade 5 (maximum development). Univariate and multiple regression analyses were conducted. RESULTS: Similar to findings in previous studies, normotensive pregnancies with a SGA fetus showed significant differences in cortical development compared with controls, with reduced Sylvian fissure depth adjusted for BPD (14.5 ± 2.4 vs 16.6 ± 2.3; P < 0.001) and increased insula depth adjusted for BPD (33.2 ± 2.0 vs 31.8 ± 2.0; P < 0.001). Interestingly, a similar cortical development pattern was observed in PE pregnancies with a SGA fetus and in PE pregnancies with an AGA fetus, manifested by reduced Sylvian fissure depth adjusted for BPD (14.2 ± 2.3 and 14.3 ± 2.3 vs 16.6 ± 2.3; P < 0.001 for both) and greater insula depth adjusted for BPD (33.2 ± 2.1 and 32.8 ± 1.7 vs 31.8 ± 2.0; P < 0.001 for both) compared with controls. No significant differences were observed in parieto-occipital, cingulate sulcus or calcarine sulcus depth across the study groups. The Sylvian fissure was scored as Grade 4 in significantly more (93.2% vs 59.5%) and as Grade 5 in significantly fewer (2.7% vs 37.3%) PE pregnancies with an AGA fetus compared with controls (P < 0.05 for both). These differences remained significant even after statistical adjustment for potential confounders, including ethnicity, low socioeconomic status, nulliparity, chronic hypertension, pregestational diabetes, assisted reproductive technologies, smoking and fetal gender, with the application of Benjamini-Hochberg procedure for multiple comparisons. CONCLUSIONS: PE with or without SGA is associated with a differential fetal cortical development pattern which is similar to that described previously in small fetuses. Future research is warranted to elucidate better the mechanism(s) underlying these changes. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

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 [International Fetal and Newborn Growth Consortium for the 21st Century standard]).Conclusion: Our finding did not support the hypothesis that 1 universal standard birthweight curve can be applied to all populations. 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 [International Fetal and Newborn Growth Consortium for the 21st Century standard]).Conclusion: Our finding did not support the hypothesis that 1 universal standard birthweight curve can be applied to all populations.

In 70% of identical twin pregnancies, the twins share a single placenta in the womb that provides them with nutrients. This shared placenta can be unequaly shared. This means that one of the twins has a much smaller share of ​​the placenta compared to the other twin, resulting in a large growth discrepancy during pregnancy, also known as 'selective fetal growth restriction'. At birth, a large difference in birth weight ensues. Sometimes one twin can be almost twice the size of the other twin.These twins are considered a vulnerable patient group in which perinatal complications are prevalent. Nevertheless, a large gap in knowledge persists, impeding proper parent counseling and risk assessment by health care providers. Simultaneously, these twins can also be considered a unique natural 'experiment' to uncover the early origins of health and disease following an adverse environment in the womb. The growth-restricted twin can be compared to a genetically identical, normally-grown twin who has been in the same womb of the same mother at the same time.In this thesis, Sophie Groene has investigated the placental mechanisms and the short- and long-term outcomes of this special group of twins.

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The opinion on the mechanisms underlying the pathogenesis of preeclampsia still divides scientists and clinicians. This common complication of pregnancy has long been viewed as a disorder linked primarily to placental dysfunction, which is caused by abnormal trophoblast invasion, however, evidence from the previous two decades has triggered and supported a major shift in viewing preeclampsia as a condition that is caused by inherent maternal cardiovascular dysfunction, perhaps entirely independent of the placenta. In fact, abnormalities in the arterial and cardiac functions are evident from the early subclinical stages of preeclampsia and even before conception. Moving away from simply observing the peripheral blood pressure changes, studies on the central hemodynamics reveal two different mechanisms of cardiovascular dysfunction thought to be reflective of the early-onset and late-onset phenotypes of preeclampsia. More recent evidence identified that the underlying cardiovascular dysfunction in these phenotypes can be categorized according to the presence of coexisting fetal growth restriction instead of according to the gestational period at onset, the former being far more common at early gestational ages. The purpose of this review is to summarize the hemodynamic research observations for the two phenotypes of preeclampsia. We delineate the physiological hemodynamic changes that occur in normal pregnancy and those that are observed with the pathologic processes associated with preeclampsia. From this, we propose how the two phenotypes of preeclampsia could be managed to mitigate or redress the hemodynamic dysfunction, and we consider the implications for future research based on the current evidence. Maternal hemodynamic modifications throughout pregnancy can be recorded with simple-to-use, noninvasive devices in obstetrical settings, which require only basic training. This review includes a brief overview of the methodologies and techniques used to study hemodynamics and arterial function, specifically the noninvasive techniques that have been utilized in preeclampsia research.

Objective To assess the degree of correlation/agreement of maternal-fetal Doppler parameters between normal and growth-restricted fetuses (fetal growth restriction [FGR]). Methods The present observational and retrospective study included 274 singleton pregnancies. The following maternal-fetal Doppler parameters were assessed: uterine artery (UAt), umbilical artery (UA), middle cerebral artery (MCA), cerebroplacental ratio (CPR), and umbilical-cerebral ratio (U/C). The assessment of FGR was based on the Figueiras and Gratacós9 criteria. Spearman correlation coefficients were estimated to assess the correlation between resistance (RI) and pulsatility (PI) indices of Doppler parameters. The agreement between two Doppler parameters was assessed by the Kappa coefficient. Results In total, 502 Doppler examinations were included, and FGR was observed in 19 out of 274 fetuses. A strong correlation was observed between RI and PI of UAt, UA, and MCA in all of the samples (p1.0 and CPR1,0 e RCp

Introduction: Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. Methods: At 116–117 days gestational age (term, 150 days), pregnant Merino ewes (n = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T2 oximetry. Results: Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. Conclusion: SC induces alterations to pulmonary haemodynamics in utero; a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale.

Socioeconomic deprivation and minority ethnic background are risk factors for adverse pregnancy outcomes. We aimed to quantify the magnitude of these socioeconomic and ethnic inequalities at the population level in England.In this cohort study, we used data compiled by the National Maternity and Perinatal Audit, based on birth records from maternity information systems used by 132 National Health Service hospitals in England, linked to administrative hospital data. We included women who gave birth to a singleton baby with a recorded gestation between 24 and 42 completed weeks. Terminations of pregnancy were excluded. We analysed data on stillbirth, preterm birth (37 weeks of gestation), and fetal growth restriction (FGR; liveborn with birthweight3rd centile by the UK definition) in England, and compared these outcomes by socioeconomic deprivation quintile and ethnic group. We calculated attributable fractions for the entire population and specific groups compared with least deprived groups or White women, both unadjusted and with adjustment for smoking, body-mass index (BMI), and other maternal risk factors.We identified 1 233 184 women with a singleton birth between April 1, 2015, and March 31, 2017, of whom 1 155 981 women were eligible and included in the analysis. 4505 (0·4%) of 1 155 981 births were stillbirths. Of 1 151 476 livebirths, 69 175 (6·0%) were preterm births and 22 679 (2·0%) were births with FGR. Risk of stillbirth was 0·3% in the least socioeconomically deprived group and 0·5% in the most deprived group (p0·0001), risk of a preterm birth was 4·9% in the least deprived group and 7·2% in the most deprived group (p0·0001), and risk of FGR was 1·2% in the least deprived group and 2·2% in the most deprived group (p0·0001). Population attributable fractions indicated that 23·6% (95% CI 16·7-29·8) of stillbirths, 18·5% (16·9-20·2) of preterm births, and 31·1% (28·3-33·8) of births with FGR could be attributed to socioeconomic inequality, and these fractions were substantially reduced when adjusted for ethnic group, smoking, and BMI (11·6% for stillbirths, 11·9% for preterm births, and 16·4% for births with FGR). Risk of stillbirth ranged from 0·3% in White women to 0·7% in Black women (p0·0001); risk of preterm birth was 6·0% in White women, 6·5% in South Asian women, and 6·6% in Black women (p0·0001); and risk of FGR ranged from 1·4% in White women to 3·5% in South Asian women (p0·0001). 11·7% of stillbirths (95% CI 9·8-13·5), 1·2% of preterm births (0·8-1·6), and 16·9% of FGR (16·1-17·8) could be attributed to ethnic inequality. Adjustment for socioeconomic deprivation, smoking, and BMI only had a small effect on these ethnic group attributable fractions (13·0% for stillbirths, 2·6% for preterm births, and 19·2% for births with FGR). Group-specific attributable fractions were especially high in the most socioeconomically deprived South Asian women and Black women for stillbirth (53·5% in South Asian women and 63·7% in Black women) and FGR (71·7% in South Asian women and 55·0% in Black women).Our results indicate that socioeconomic and ethnic inequalities were responsible for a substantial proportion of stillbirths, preterm births, and births with FGR in England. The largest inequalities were seen in Black and South Asian women in the most socioeconomically deprived quintile. Prevention should target the entire population as well as specific minority ethnic groups at high risk of adverse pregnancy outcomes, to address risk factors and wider determinants of health.Healthcare Quality Improvement Partnership.

Objective We sought to investigate the positive predictive value of ultrasound-diagnosed fetal growth restriction (FGR) for estimating small for gestational age (SGA) at birth. Secondary objectives were to describe clinical interventions performed as a result of FGR diagnosis. Study Design This was a retrospective cohort of pregnancies diagnosed with FGR over 3 years at a single institution. Maternal demographics, antenatal and delivery data, and neonatal data were collected. Descriptive statistics and linear regression were conducted. Results We included 406 pregnancies with diagnosis of FGR in second or third trimester. Median birth weight percentile was 17 (interquartile range: 5–50) and only 35.0% of these fetuses were SGA at birth. The positive predictive value of a final growth ultrasound below the 10th percentile for SGA at birth was 56.9%. Patients averaged eight additional growth ultrasounds following FGR diagnosis. One hundred and fourteen (28.1%) received antenatal steroids prior to delivery, and 100% of those delivered after more than 7 days following administration. There were 6 fetal deaths and 14 neonatal deaths. Conclusion In the majority of cases, pregnancies diagnosed with FGR during screening ultrasounds resulted in normally grown neonates and term deliveries. These patients may be receiving unnecessary ultrasounds and premature courses of corticosteroids.

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

Catastrophic antiphospholipid syndrome (CAPS) is an uncommon and the most severe form of antiphospholipid syndrome (APS). A 33-week pregnant patient with Klippel-Trenaunay syndrome, past SARS-CoV-2 infection and type I fetal growth restriction with shortening of the fetal long bone was diagnosed in our center with a probable CAPS. Cesarean section was performed four days after the diagnosis due to the torpid evolution of the patient. Clinical improvement was noted a few days later and the mother and baby were discharged within a week. We review the current literature on CAPS during pregnancy and provide an updated view.

This study evaluated the damage to the endothelial tight junctions (TJs) in pregnancies complicated by fetal growth restriction (FGR) and investigated whether FGR is related to blood–brain barrier disintegration and, subsequently, to the appearance of proteins indicative of neuronal injury in maternal blood. The studied group included 90 pregnant women diagnosed with FGR. The control group consisted of 70 women with an uncomplicated pregnancy. The biochemical measurements included serum neuronal proteins (subunit of the N-methyl-D-aspartate receptor—NR1, nucleoside diphosphate kinase A—NME1, and S100 calcium-binding protein B—S100B), serum TJ proteins (occludin—OCLN, claudin-5—CLN5, zonula occludens—zo-1, and OCLN/zo-1 and CLN5/zo-1 ratios), and placental expression of TJ proteins (OCLN, claudin-4 CLN4, CLN5, zo-1). The significantly higher serum S100B and CLN5 levels and serum CLN5/zo-1 ratio were observed in FGR compared to healthy pregnancies. Moreover, FGR was characterized by increased placental CLN5 expression. Both serum NME1 levels and placental CLN4 expression in FGR pregnancies were significantly related to the incidence of neurological disorders in newborns. Mothers of FGR neonates who developed neurological complications and intraventricular hemorrhage (IVH) had statistically higher NME1 concentrations during pregnancy and significantly lower placental CLN4 expression than mothers of FGR neonates without neurological abnormalities. The serum NME1 levels and placental CLN4 expression were predictive markers of IVH in the FGR group. The blood–brain barrier is destabilized in pregnancies complicated by FGR. Neurological disorders, including IVH, are associated with higher serum concentrations of NME1 and the decreased placental expression of CLN4. The serum NME1 levels and placental CLN4 expression may serve as biomarkers, helpful in predicting IVH in FGR. It may allow for more precise monitoring and influence decision-making on the optimal delivery time to avoid developing neurological complications.

Prospective pregnancy cohort in Lusaka, Zambia

The risk of adverse birth outcomes is higher in birthing people with a prior adverse birth outcome including stillbirth, preterm birth, and neonatal mortality. Studies from national registries and hospital data from countries like the United States (U.S.), Sweden, Netherlands, Australia, India, China, and Tanzania have shown that having one of these outcomes increases the risk of having a similar subsequent adverse outcome. While global systematic reviews support these findings, there are country-specific disparities that need further exploration. In the U.S., for example, the rate of stillbirth recurrence is three times higher among Black birthing people than among White people. Other race-based comparisons show that Black people with stillbirth in their first pregnancy had four times the risk of a subsequent neonatal death compared to Black people with no prior stillbirth; for White people with previous stillbirth, this risk was twice as high compared to White women with a live term first birth (Sharma et al.). Therefore, this review of studies from the U.S. will quantify the risk of recurrence of adverse birth outcomes and identify risk factors that might produce disparities in these outcomes. To account for an adequate pool of studies to review, we will focus on six adverse outcomes and recurrent cross-outcomes.

(1) Aim: Ultrasound is the gold standard for assessing fetal growth disorders. The relationship between high sFlt-1/PlGF scores and LBW (low birth weight) was described. In this study, we attempted to assess whether uric acid could be used as a secondary marker in estimating the pregnancy risk associated with LBW. (2) Material and methods: 665 pregnant women with a suspected or confirmed form of placental insufficiency were enrolled. In each of the patients, sFlt-1 and PlGF and uric acid levels were determined. Patients were divided into two groups according to birth weight below and above the third percentile for the given gestational age with the criteria of the neonatal definition of FGR (fetal growth restriction). (3) Results: A significant negative correlation between neonatal birth weight and the uric acid level across the entire study group was observed. We found a significant negative correlation between neonatal birth weight and the uric acid level with birth weights < 3rd percentile. (4) Conclusions: There is a significant link between the uric acid concentration and LBW in the group with placental insufficiency. Uric acid can improve the prediction of LBW. An algorithm for LBW prognosis that makes use of biophysical (ultrasound) and biochemical (uric acid level, angiogenesis markers) parameters yields better results than using these parameters separately from each other.

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology. ispartof: INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH vol:19 issue:18 ispartof: location:Switzerland status: published

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 and Objectives: Tadalafil is expected to treat fetal growth restriction (FGR), a risk factor for stillbirth and neonatal morbidity. This study aimed to evaluate the fetal biometric growth pattern of fetuses with FGR treated with tadalafil by ultrasonographic assessment. Materials and Methods: This was a retrospective study. Fifty fetuses diagnosed with FGR and treated by maternal administration of tadalafil and ten controls who received conventional treatment at Mie University Hospital from 2015 to 2019 were assessed. Fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) at the start of treatment and at two weeks and four weeks of treatment were mainly assessed by ultrasound examination. The Wilcoxon signed-rank test was used to assess the measures. The Kyoto Scale of Psychological Development (KSPD) was used to assess the developmental prognosis on tadalafil-treated children at 1.5 years of corrected age (CA) and 3 years old. Results: The median gestational age at the start of treatment was 30 and 31 weeks in the tadalafil and control groups, respectively, and the median gestational age at delivery was 37 weeks in both groups. The Z-score of HC was significantly increased at 4 weeks of treatment (p = 0.005), and the umbilical artery resistance index was significantly decreased (p = 0.049), while no significant difference was observed in the control group. The number of cases with an abnormal score of less than 70 on the KSPD test was 19% for P-M, 8% for C-A, 19% for L-S, and 11% for total area at 1.5 years CA. At 3 years old, the respective scores were 16%, 21%, 16%, and 16%. Conclusions: Tadalafil treatment for FGR may maintain fetal HC growth and infants’ neuro-developmental prognosis.

Background and Objectives: Fetal growth abnormalities increase the risk of negative perinatal and long-term outcomes. Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical to which humans may be exposed in a number of ways, such as from the environment, via various consumer products, and through the individual’s diet. Since the compound possesses estrogen-mimicking properties and exerts epigenetic and genotoxic effects, it has been associated with harmful effects impacting the entire spectrum of human life, including, vitally, the intrauterine period. We investigated the role of maternal exposure to BPA in abnormal fetal growth velocity, both impaired and excessive. Materials and Methods: Amniotic fluid samples were collected from 35 women who underwent amniocentesis early in the second trimester due to medical reasons. Pregnancies were followed until delivery, and birth weights were recorded. The amniotic fluid samples were subsequently divided into three groups based on fetal birth weight, as follows: AGA (appropriate for gestational age), SGA (small for gestational age), and LGA (large for gestational age). Amniotic fluid BPA levels were determined by gas chromatography coupled with mass spectrometry. Results: BPA was detected in 80% (28/35) of our amniotic fluid samples. Median concentration was 281.495 pg/mL and ranged from 108.82 pg/mL to 1605.36 pg/mL. No significant association was observed between the study groups regarding BPA concentration. A significant positive correlation between amniotic fluid BPA concentration and birth weight centile (r = 0.351, p-value = 0.039) was identified. BPA levels were also inversely associated with gestational age in pregnancies at term (between 37 and 41 weeks) (r = −0.365, p-value = 0.031). Conclusions: Our findings suggest that maternal exposure to BPA during the early second trimester of pregnancy can potentially contribute to increased birthweight percentiles and to decreased gestational age in pregnancies at term.

Fetal growth restriction associated with continued maternal sirolimus therapy in pregnancy has not been reported. We hereby present a case of maternal sirolimus therapy resulting in fetal growth restriction and propose a multi-hit model. This hypothetic model is based on inhibition of mTOR signaling pathway and epigenetic modulation. This case report adds to the paucity of literature on continued monotherapeutic maternal sirolimus in pregnancy and its adverse fetal effects.

Objective To describe the short‐ and long‐term outcomes of infants with early‐onset fetal growth restriction (FGR) and umbilical artery absent or reversed end‐diastolic flow (AREDF), delivered before 30 weeks' gestation and managed proactively. Methods This was a retrospective cohort study of fetuses delivered for fetal indication before 30 completed weeks' gestation that had early‐onset FGR (defined as estimated fetal weight more than 2 SD below the mean) with AREDF in the umbilical artery (FGR group), at the level‐3 perinatal unit in Lund, Sweden, between 1998 and 2015. Perinatal outcome and neurodevelopment at ≥ 2 years of age in surviving infants were compared with those of a group of infants without small‐for‐gestational‐age birth weight or any known fetal Doppler changes delivered before 30 weeks in Lund during the corresponding time period (non‐FGR group). In the FGR group, the main indication for delivery was the Doppler finding of AREDF in the umbilical artery. Results There were 139 fetuses (of which 26% were a twin/triplet) in the FGR group and 946 fetuses (of which 28% were a twin/triplet) in the non‐FGR group. The FGR infants had a median birth weight of 630 g (range, 340–1165 g) and gestational age at birth of 187 days (range, 164–209 days), as compared with 950 g (range, 470–2194 g) and 185 days (range, 154–209 days), respectively, in the non‐FGR group. The rate of fetal mortality did not differ between the two groups (5.0% and 5.4% in the FGR and non‐FGR groups, respectively). All seven intrauterine deaths in the FGR group occurred before 26 weeks' gestation. In the FGR group compared with the non‐FGR group, severe intraventricular hemorrhage was less frequent and bronchopulmonary dysplasia and septicemia were more frequent (P = 0.008, P

Due to the morbidity of mothers and newborns caused by fetal growth restriction (FGR) and preeclampsia, preventive measures should be taken, especially in women at high risk of developing these conditions. Many studies have been conducted on the prevention of FGR and preeclampsia in high-risk women, especially anticoagulants, aspirin, paravastatin, nitric oxide, microelements (L-arginine, folic acid, vitamins E and C, phytonutrients, vitamin D) and calcium. The aim is to improve perinatal consequences by preventing FGR in high-risk women. Materials and methods: A prospective study of 137 pregnant women in the period of 110–136 weeks was conducted at the Perinatal Center in Kyiv. Pregnant women were divided into 3 groups. The main group included 47 women at high risk of FGR who received therapy (low doses of aspirin, low molecular weight heparin (LMWH) and vitamin and micro elements drugs). The comparison group included 45 women who had a high risk of FGR but did not receive treatment. The control group consisted of 45 women who were not at risk of FGR. The frequency of FGR and placental dysfunction were analyzed as well as a fetal distress was analyzed ante- and intranatally. Results: Therapy with low doses of aspirin, LMWH and a complex preparation of vitamins and micro elements improves the course of pregnancy and gestational complications. In the main group FGR was detected in 8.5 %, in the comparison group – in 17.8 %, in the control group – 4.4 %. Placental dysfunction was detected in 13.3 % in the control group, and only 6.4 % in the main group that was close to the control group – 2.2 %. Similar tendencies were found for fetal distress ante- and intranatally. Conclusions: The proposed prophylactic measures can improve maternal outcomes by reducing the level of gestational complications in pregnant women with biochemical signs of risk of FGR development. In addition, these preventive measures can reduce the frequency of children births with growth restriction, which significantly reduces early neonatal and perinatal morbidity and mortality.

Objective The primary outcome was to compare the diagnostic accuracy of neonatal small for gestational age (SGA) by the Hadlock and Fetal Medicine Foundation (FMF) charts in our cohort, followed by the ability to predict composite severe neonatal outcomes (SNO) in pregnancies with preterm prelabor rupture of membranes (PPROM). Methods This study was a secondary analysis of a prospective cohort of pregnancies with PPROM from 2015 to 2018, from 23 to 36 completed weeks of gestation. Sensitivity, specificity, and positive and negative predictive values for the primary and secondary outcomes of the Hadlock and FMF fetal charts were calculated. The discriminatory ability of each chart was compared using the area under the receiver’s operating curves of clinical characteristics. Results Of the 106 women who met the inclusion criteria, 48 (45%) were screened positive using the FMF fetal growth chart and 22 (21%) were screened positive using the Hadlock chart. SGA was diagnosed in 12 infants (11%). Both fetal growth charts had comparable diagnostic accuracies and were statistically significant predictors of SGA (Hadlock: area under the receiver operating characteristic curves [AUC], 0.76, risk ratio [RR], 7.6, 95% confidence interval [CI], 2.5–23; and FMF: AUC, 0.76 RR, 13.3 95%CI 1.8–99.3). Both growth standards were poor predictors of SNO. Conclusion The Hadlock and FMF fetal growth charts have a similar accuracy to predict SGA in pregnancies complicated by PPROM. The FMF fetal growth chart may result in a 2-fold increase in positive screens, potentially increasing fetal surveillance.

To improve identification of fetal growth restriction (FGR) by means of umbilical venous flow (QUV) and maternal hemodynamics, including systemic vascular resistance (SVR) and cardiac output (CO), in order to distinguish between FGR and SGA.We enrolled 68 pregnancies (36 SGA, 8 early FGR and 24 late FGR) who underwent a complete fetal hemodynamic examination including QUV and a noninvasive maternal hemodynamics assessment by means of USCOM.In comparison with SGA, QUV and corrected for estimated fetal weight QUV (cQUV) were significantly lower in early and late-FGR. In addition, maternal CO was lower in early and late-FGR, while SVR was lower only in early-onset FGR. According to ROC analysis, cQUV centile (AUC 0.92, 0.72) was the best parameter for the prediction of SGA before and after 32 weeks, followed by SVR and CO. For all parameters, the prediction was always better in the case of early-onset FGR32 weeks.UV flow and maternal hemodynamics examination are useful tools to accurately discern between SGA and FGR.

Fetal growth restriction can affect health outcomes in postnatal life. This study tested the hypothesis that the response to an inflammatory pulmonary insult is altered in pediatric fetal growth restricted rats. Using a low-protein diet during gestation and postnatal life, growth-restricted male and female rats and healthy control rats were exposed to an inflammatory insult via the intratracheal instillation of heat-killed bacteria. After 6 h, animal lungs were examined for lung inflammation and status of the surfactant system. The results showed that in response to an inflammatory insult, neutrophil infiltration was decreased in both male and female rats in the growth-restricted animals compared with the control rats. The amount of surfactant was increased in the growth-restricted animals compared with the control rats, regardless of the inflammatory insult. It is concluded that fetal growth restriction results in increased surfactant and altered neutrophil responses following pulmonary insult.

Objective Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID‐19 (PAN‐COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal–Perinatal Medicine (SONPM) National Perinatal COVID‐19 Registry. Methods This was an analysis of data from the PAN‐COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS‐CoV‐2 infection at any stage in pregnancy, and the AAP‐SONPM National Perinatal COVID‐19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS‐CoV‐2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN‐COVID results are presented overall for pregnancies with suspected or confirmed SARS‐CoV‐2 infection and separately in those with confirmed infection. Results We report on 4005 pregnant women with suspected or confirmed SARS‐CoV‐2 infection (1606 from PAN‐COVID and 2399 from AAP‐SONPM). For obstetric outcomes, in PAN‐COVID overall and in those with confirmed infection in PAN‐COVID and AAP‐SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (

Objective: Our objective was to compare differences in Doppler blood flow in four fetal intracranial blood vessels in fetuses with late-onset fetal growth restriction (FGR) vs. those with small for gestational age (SGA). Methods: Fetuses with estimated fetal weight (EFW)

Objectives We aim to investigate the utility of middle cerebral artery peak systolic velocity (MCA PSV) Doppler in determining the perinatal mortality and morbidity in serial Doppler measurements from the time of diagnosis to the delivery of complicated cases with fetal growth restriction (FGR). Methods At 24–38 weeks of gestation, 65 pregnant women diagnosed with FGR were included in the study. The fetal biometry measurements, MCA pulsatility index (PI), and MCA PSV Doppler evaluation of the cases formed at the diagnosis and the delivery were recorded. Gestational weeks, birth weights, APGAR scores, cord pH values, NICU (neonatal intensive care unit) admission, NICU duration of stay, and perinatal morbidity parameters such as RDS (respiratory distress syndrome), BPD (bronchopulmonary dysplasia), NEC (necrotizing enterocolitis), sepsis and perinatal mortality were compared. The patients were divided into two groups: early and late-onset fetal growth restriction. Perinatal morbidity and mortality were accepted as adverse perinatal outcomes. Results MCA PSV above the 95th percentile at the diagnosis and delivery time was seen at a significantly higher rate with adverse perinatal outcomes. Conclusions This study shows that evaluating MCA PSV with Doppler can be a helpful diagnostic method for early diagnosis of restriction and hypoxic fetuses. Also, it may be used in clinics as a noninvasive method to predict neonatal prognosis.

In this study, our aims were to characterize oligodendrogenesis alterations in fetuses with intrauterine growth restriction (IUGR) and to find therapeutic strategies to prevent/treat them using a novel rabbit in vitro neurosphere culture. IUGR was surgically induced in one uterine horn of pregnant rabbits, while the contralateral horn served as a control. Neural progenitor cells (NPCs) were obtained from pup’s whole brain and cultured as neurospheres mimicking the basic processes of brain development including migration and cell differentiation. Five substances, chosen based on evidence provided in the literature, were screened in vitro in neurospheres from untreated rabbits: Docosahexaenoic acid (DHA), melatonin (MEL), zinc, 3,3′,5-Triiodo-L-thyronine (T3), and lactoferrin (LF) or its metabolite sialic acid (SA). DHA, MEL and LF were further selected for in vivo administration and subsequent evaluation in the Neurosphere Assay. In the IUGR culture, we observed a significantly reduced percentage of oligodendrocytes (OLs) which correlated with clinical findings indicating white matter injury in IUGR infants. We identified DHA and MEL as the most effective therapies. In all cases, our in vitro rabbit neurosphere assay predicted the outcome of the in vivo administration of the therapies and confirmed the reliability of the model, making it a powerful and consistent tool to select new neuroprotective therapies.

Fetal growth restriction (FGR) is defined as fetuses who have failed to achieve a normal weight for gestational age. FGR is associated with adverse perinatal outcomes, including stillbirth. Pregnant women often perceive decreased fetal movements before intrauterine fetal death. Previous reports on the association between fetal movements and FGR have mainly targeted livebirths, with few focusing on stillbirths. Studying stillbirths, not livebirths, may help improve perinatal adverse outcomes. This study evaluated the association between FGR leading to stillbirth and maternal perception of decreased fetal movement. This was a population-based study reviewing all stillbirths in Shiga Prefecture, Japan for 10 years. We analyzed 219 stillbirth cases, those with versus without FGR. We then compared maternal visits to healthcare providers due to perception of decreased fetal movement between these two groups. There were 82 stillbirths with FGR, and the remaining 137 stillbirth were without FGR. Women with FGR, compared with those without, were significantly less often to visit the outpatient department due to decreased fetal movement (30%; 25/82 vs. 46%; 63/137: P = 0.034). Pregnant women have more difficulty perceiving decreased fetal movements in cases with severe FGR than in those without FGR. Healthcare providers, including midwives, may need to closely monitor FGR pregnancy in addition to instructing pregnant women to be aware of decreased fetal movement.

The presence of multiple large (>1 Mb) copy number variants (CNVs) in non‐malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4–3.9 Mb de novo duplications. We found that the duplications likely co‐localized to the same cells, were mosaic in the placenta, and impacted maternal and paternal chromosomes. In addition, 27.4 Mb and 240 genes were duplicated in affected cells, including candidate placental genes KISS1 and REN. We ruled out involvement of homologous recombination‐based mechanisms or an altered epigenome in generating the CNVs. This case highlights the diversity of genetic abnormalities in the human placenta and the gaps in our knowledge of how such errors arise.

One strategy for improving detection of fetal growth restriction (FGR) is developing biosensors identifying placental dysfunction as a leading pathogenesis for FGR. The aim of this pilot study was to investigate the performance of a biosensor specified to detect placental dysfunction by means of maternal arterial turbulence acoustics in a low-resource setting. A cohort of 147 singleton pregnant women were prospectively followed with double-blinded biosensor tests, sonographic estimation of fetal weight (EFW) and Doppler flow at 26–28, 32–34 and 37–39 weeks of pregnancy. Full term live births with recorded birth weights (BWs) and without major congenital malformations were included. Outcomes were defined as (A) a solitary biometric measure (BW &lt, 3rd centile) and as (B) a biometric measure and contributory functional measure (BW &lt, 10th centile and antenatally detected umbilical artery pulsatility index &gt, 95th centile). Data from 118 women and 262 antenatal examinations were included. Mean length of pregnancy was 40 weeks (SD ± 8 days), mean BW was 3008 g (SD ± 410 g). Outcome (A) was identified in seven (6%) pregnancies, whereas outcome (B) was identified in one (0.8%) pregnancy. The biosensor tested positive in five (4%) pregnancies. The predictive performance for outcome (A) was sensitivity = 0.29, specificity = 0.97, p = 0.02, positive predictive value (PPV) was 0.40 and negative predictive value (NPV) was 0.96. The predictive performance was higher for outcome (B) with sensitivity = 1.00, specificity = 0.97, p = 0.04, PPV = 0.20 and NPV = 1.00. Conclusively, these pilot-study results show future potential for biosensors as screening modality for FGR in a low-resource setting.

Objectives The primary objective was the identification of sub-standard care in antepartum stillbirths in Emilia-Romagna Region (Italy), hence the number of potentially preventable cases. Secondly, we seek to evaluate any association between inadequate care and either risk factors for stillbirth or causes of death. Study Design This study was based on prospectively-collected data in an institutional stillbirth audit project, involving all 29 hospital with a maternity unit in Emilia-Romagna Region. For each stillbirth occurred in the area from 2014 to the first semester of 2019 the same diagnostic workup was performed and a clinical record with data about mother and stillborn was completed. Every case was discussed in a multidisciplinary local audit to assess both the cause of death and the quality of care. Two aspects of care quality were evaluated: clinical management and women’s access to care. Data were then reviewed by the Regional Audit Group. Results Elements of inadequate care were identified in 56 out of 524 (10.7 %) fetal deaths. Non-Italian women and pregnancies with fetal growth restriction had double the risk of having received inadequate care during pregnancy, compared to Italian women (aOR 2.0, 95 % CI 1.1–3.6) and a normally developing fetus (aOR 2.0, 95 % CI 1.1–4.1), respectively. Women whose stillbirth was caused by maternal disorders were at higher risk for inadequate care compared to women who had stillbirth explained by other cause (aOR 5.89, 95 %CI 2.2–15.4). Sub-optimal clinical management and barriers to access to care were observed to equal extents. Inappropriate ultrasound monitoring was the most frequent suboptimal care element. Conclusions About one out of ten stillbirths was potentially preventable. Interventions to reduce stillbirth occurrence in our high-resource setting should focus on appropriate diagnosis and management of maternal disorders and fetal growth restriction, as well as improving access to antenatal care.

Objective: We previously provided evidence to confirm that maternal serum levels of soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this secondary analysis, we further examine the potential additive value of maternal serum Inhibin-A, which is a hormone marker of the transforming growth factor family, to the accuracy provided by maternal serum PlGF and sFlt-1. Methods: We conducted a secondary analysis where we extracted the data of a cohort of 125 pregnant women enrolled near delivery at the clinics of the University Medical Center of Ljubljana, Slovenia. The dataset included 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 10 of PE, 12 of FGR, 28 of PE+FGR, and 6 of PTD. In addition to the recorded demographic characteristics and medical history and the maternal serum levels of PlGF and sFlt-1/PlGF ratio, which were previously published, we evaluated the added value of maternal serum Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations were estimated from areas under the curve (AUC) of receiver operating characteristics (ROC) curves, Box and Whisker plots, and by multiple regression. We estimated accuracy by the continuous marker model and a cutoff model. Results: In this study, we combined Inhibin-A with PlGF or with the sFlt-1/PlGF ratio and showed a 10–20% increase in AUCs and 15–45% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR and FGR in all cases but not for FGR in early cases delivered &lt, 34 weeks. The use of a cutoff model was adequate, although a bit higher accuracy was obtained from the continuous model. The highest correlation was found for PlGF with all three complications. Conclusion: In this secondary analysis, we have found that maternal serum Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by maternal serum angiogenic markers alone, bringing the results to a diagnostic level, thus, it could be considered for directing clinical management. Inhibin-A had smaller or no added value for the accuracy of predicting FGR alone, mainly of early cases delivered &lt, 34 weeks.

The purpose of this study was to evaluate the function and possible mechanism of miR-212-3p in fetal growth restriction (FGR) and to demonstrate the relationship between miR-212-3p and placental growth factor (PGF). First, we used qRT-PCR to detect the expression of miR-212-3p and PGF in placental tissues of normal delivery (HC group) and FGR, as well as in human trophoblast cell HTR-8/Svneo. The results revealed that miR-212-3p expression was significantly upregulated and PGF was significantly downregulated in placental tissue in the FGR group compared with the HC group. In addition, interference with miR-212-3p expression increased the proliferation, invasion, and migration of HTR-8/SVneo cells and decreased apoptosis of cells. Meanwhile, Western blot results showed that miR-212-3p expression downregulation promoted the phosphorylated protein expression of Phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), which in turn activated the PI3K/AKT signaling pathway. And the results of dual luciferase reporter further showed that miR-212-3p could target PGF, and the expression of both was negatively correlated in FGR group tissues. In addition, downregulation of miR-212-3p expression reversed the inhibitory effect of PGF downregulation on HTR-8/SVneo cells. In conclusion, miR-212-3p can target and inhibit the PGF expression and regulate the PI3K/AKT signaling pathway to regulate trophoblast cell invasion, migration, proliferation and cell apoptosis. This provides a potential biomarker for the development of FGR.

Ultrasonography and fetal heart rate monitoring are subjective assessments of fetal condition, which warrants the need for objective markers to predict fetal condition. Urinary L-type fatty acid-binding protein (L-FABP) levels correlate with hypoperfusion. Elevated amniotic fluid L-FABP levels may represent fetal tissue hypoperfusion since the amniotic fluid contains fetal urine. In this study, we aimed to analyze the effectiveness of amniotic fluid L-FABP as a predictor of fetal condition. We classified singleton pregnancies into groups based on fetal growth restriction (FGR) with and without fetal blood flow abnormalities (FGR and healthy-FGR groups, respectively) and the non-FGR group (control group). We collected amniotic fluid at the time of vaginal delivery, cesarean section and amniocentesis, and compared the patient characteristics, clinical outcomes and amniotic fluid levels of L-FABP between the groups. We analyzed 153 singleton pregnancies and 186 amniotic fluid samples (FGR group, 6 (3.9%) pregnancies and 23 (12.4%) samples; healthy-FGR group, 15 (9.8%) pregnancies and 20 (10.7%) samples; control group, 132 (86.3%) pregnancies and 143 (76.9%) samples). The amniotic fluid L-FABP level was significantly higher in the FGR group compared to that in the healthy-FGR and control groups. Multivariate analysis revealed that the amniotic fluid L-FABP level was not affected by fetal body weight. Additionally, the amniotic fluid L-FABP levels increased significantly in cases with fetal blood flow abnormalities or early gestational age. Therefore, amniotic fluid L-FABP level may be an objective and accurate predictive marker of fetal condition.

We aimed to determine the impact of high-fructose intake during pregnancy on the fetal-placental unit in rats, which may be the initial mechanism of the programming effect of fructose. Pregnant Sprague–Dawley rats were randomly assigned to three groups and respectively provided tap water (n = 10), 10% (w/v) fructose solution (n = 10), and 10% (w/v) glucose solution (n = 10) from embryonic day 0 to 20. Compared with the control and glucose groups, significantly lower fetal length, fetal weight, placental weight, and fetus/placenta ratio were found in the fructose group on embryonic day 20 (all p

Congenital cytomegalovirus infection (cCMV) can cause fetal growth restriction (FGR) and severe sequelae in affected infants. Clinicians generally suspect cCMV based on multiple ultrasound (US) findings associated with cCMV. However, no studies have assessed the diagnostic accuracy of fetal US for cCMV-associated abnormalities in FGR. Eight FGR and 10 non-FGR fetuses prenatally diagnosed with cCMV were examined by undergoing periodic detailed US examinations, as well as postnatal physical and imaging examinations. The diagnostic accuracy of prenatal US for cCMV-associated abnormalities was compared between FGR and non-FGR fetuses with cCMV. The diagnostic sensitivity rates of fetal US for cCMV-related abnormalities in FGR vs. non-FGR fetuses were as follows: ventriculomegaly, 66.7% vs. 88.9%; intracranial calcification, 20.0% vs. 20.0%; cysts and pseudocysts in the brain, 0% vs. 0%; ascites, 100.0% vs. 100.0%; hepatomegaly, 40.0% vs. 100.0%; splenomegaly, 0% vs. 0%. The diagnostic sensitivity of fetal US for hepatomegaly and ventriculomegaly in FGR fetuses with cCMV was lower than that in non-FGR fetuses with cCMV. The prevalence of severe long-term sequelae (e.g., bilateral hearing impairment, epilepsy, cerebral palsy, and severe developmental delay) in the CMV-infected fetuses with FGR was higher, albeit non-significantly. Clinicians should keep in mind the possibility of overlooking the symptoms of cCMV in assessing fetuses with FGR.

Resume Objectifs Selon le concept des « origines developpementales de la sante et des maladies », l’obesite maternelle predispose la descendance aux maladies chroniques. Pour de multiples raisons, une perte de poids preconceptionnelle est recommandee aux femmes obeses. Cependant, les avantages et les potentiels inconvenients pour l’enfant a naitre sont encore mal etudies. Methodes Nous avons evalue le developpement fœtal et analyse l’expression de modificateurs epigenetiques et de genes metaboliques dans le foie et le placenta. Les descendants nes de mere « controle », « obese » ou « perte de poids » ont ete soumis apres le sevrage a un regime controle ou hyperlipidique. Nous avons suivi les parametres metaboliques et les comportements olfactifs jusqu’a l’âge adulte. Resultats Les fœtus de mere obese presentent une restriction de croissance et une alteration de l’expression de modificateurs epigenetiques de la voie d’acetylation des histones. Les phenotypes metaboliques et olfactifs (obesite, dyslipidemie, intolerance au glucose et faible motivation et capacite a trouver une recompense alimentaire) s’expliquent principalement par le regime post-sevrage, mais l’obesite maternelle a un effet notable de conditionnement dependant du sexe : les mâles nes de mere obese developpent une obesite accrue par rapport a leurs congeneres. La perte de poids preconceptionnelle normalise les phenotypes fœtaux et metaboliques decrits ci-dessus, mais certains genes restent differentiels. De plus, elle a des effets inattendus sur les performances olfactives : la sensibilite olfactive peripherique et la motivation induite par le jeune sont reduites. Conclusions Nos resultats confirment les avantages d’une perte de poids preconceptionnelle pour la sante metabolique des descendants, mais revelent de potentiels effets indesirables tels qu’observes pour le comportement olfactif.

Introduction: Fetal growth restriction is associated with adverse perinatal outcome and the clinical management of these pregnancies is a challenge. The aim of this study was to investigate the potential of cerebroplacental ratio (CPR) to predict adverse perinatal outcome in high-risk pregnancies in the third trimester. Another aim was to study whether the CPR has better predictive value than its components, middle cerebral artery (MCA) pulsatility index (PI) and umbilical artery (UA) PI. Material and methods: The study was a retrospective cohort study including 1573 singleton high-risk pregnancies with Doppler examinations performed at 32+0 to 40+6 gestational weeks at Lund University Hospital and the University Hospital of Malmo between 29 December 1994 and 31 December 2017. Receiver operating characteristics (ROC) curves were used to investigate the predictive value of the gestational age-specific z-scores for CPR, UA PI and MCA PI, respectively, for the primary outcome “perinatal asphyxia/mortality” and the secondary outcomes “birthweight small for gestational age (SGA)” and two composite outcomes: “appropriate for gestational age/large for gestational age liveborn infants with neonatal morbidity” and “SGA liveborn infants with neonatal morbidity.”. Results: The performance in predicting perinatal asphyxia/mortality was poor for all three variables and did not differ significantly. The ROC area under curve (AUC) was 0.56, 0.55 and 0.53 for CPR, UA PI and MCA PI z-scores, respectively. The ROC AUC for CPR z-scores to predict SGA was 0.73, significantly higher than that for either UA PI or MCA PI (P

Background Pregnant women are currently offered two ultrasound scans, one at booking (around 12 weeks��� gestation) and one at around 20 weeks��� gestation. No further scans are offered unless there are clinical indications. Ultrasound has an important role in the management of high-risk pregnancies. However, there is no clear evidence that it is effective in screening low risk and unselected women. The majority of complications, such as stillbirth and shoulder dystocia occur in low-risk pregnancies, first because most pregnancies are classified as low-risk and second, possibly due to inadequate screening. An effective ultrasound screening programme in late pregnancy combined with an intervention, like induction of labour, for the screen positives could potentially improve pregnancy outcomes. However, the diagnostic accuracy of many ultrasonic features is unknown in low-risk populations and there is a possibility of iatrogenic harm by intervening when it is not necessary. Objectives 1. To assess the diagnostic effectiveness of late pregnancy ultrasound in nulliparous women based on the existing research literature. 2. To analyse the prospective cohort study, Pregnancy Outcome Prediction Study, for the above ultrasound findings and combine the results with the meta-analyses. 3. Finally, use the results to provide inputs for health economic analyses of the cost-effectiveness of universal ultrasound screening and assess the need, potential design, and acceptability of a future randomised controlled trial. Methods The following key ultrasound measurements were identified which might be used in late pregnancy screening: (i) suspected small for gestational age (SGA), (ii) suspected large for gestational age (LGA), (iii) high resistance pattern of umbilical artery Doppler flow velocimetry, (iv) low cerebro-placental ratio (CPR), (v) severe oligohydramnios, (vi) borderline oligohydramnios. I found that there was an on-going Cochrane Diagnostic Test Accuracy review for SGA, hence I focused on the other five measures. The protocol was registered with the PROSPERO register of systematic reviews (CRD42017064093). Medline, EMBASE, Clinical Trials.gov and the Cochrane library were searched from inception. Studies that performed an ultrasound scan ���24 weeks of gestational age in unselected, low or mixed risk populations were included, excluding studies which only included high risk pregnancies. The risk of bias in each included study was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS 2) tool. Meta-analysis was performed using the hierarchal summary receiver operating characteristic curve (HSROC) analysis and bivariate logit-normal models. I also performed new analyses on previously unpublished data of the Pregnancy Outcome Prediction (POP) study which was one of the few studies that blinded ultrasound scan results to the clinicians. Results 41 studies of LGA met our inclusion criteria involving 112,034 patients in total. Ultrasonic suspicion of fetal macrosomia was strongly predictive of the risk of delivering a large baby with the positive LRs (LR+) ranging from 7 to 12. However, it was only weakly predictive of the risk of shoulder dystocia with LR+ around 2. 13 studies of umbilical artery (UA) Doppler that met our inclusion criteria including 67,764 patients in total. UA Doppler had weak/moderate predictive accuracy for detecting SGA and severely SGA (

Alterations in intrauterine fetal growth increase the risk of adverse perinatal and neonatal outcomes. In this retrospective study, we analyzed data of 906 pregnancies collected in our maternal fetal medicine center, with different patterns of growth: 655 AGA (Appropriate for Gestational Age), 62 SGA (Small for Gestational Age: fetuses born with a weight less than 10° centile, not diagnosed before delivery), 189 FGR (Fetal Growth Restriction, classified in early and late according to gestational week at diagnosis). For each group, we compared maternal characteristics, gestational age at delivery, and perinatal and neonatal outcomes. Risk factors for fetal growth alterations were advanced age, being primiparous, and a lower pregestational BMI. FGR fetuses were born at earlier gestational ages (32 [IQR 29-38] early-FGR and 38 [IQR 36-39] late-FGR), with blood gas values comparable to the AGA group but worse neonatal outcomes related to prematurity. Unexpected SGA fetuses born by vaginal delivery, managed as AGA, were more hyperlactacidemic (4.4 [IQR 2.7-5.5]) and hypoxemic (-5.0 [IQR -7.1-2.8]) at birth than both AGA and FGR. However, neonatal outcomes (accesses and days of hospitalization in NICU) were better than FGR, likely due to gestational age and birthweight similar to AGA.

Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long-chain fatty acylcarnitines compared with controls (C14: CTRL 0.012 ± 0.005 nmol/ml vs. IUGR 0.018 ± 0.005 nmol/ml, P < 0.05; C18: CTRL 0.027 ± 0.009 nmol/mol vs. IUGR 0.043 ± 0.024 nmol/mol, P < 0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY-C12-saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), β-oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of the lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium (P < 0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency.