Early Fetal Growth Restriction with or Without Hypertensive Disorders: a Clinical Overview.

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR.

Hypertensive Disorders of Pregnancy and Fetal Growth Restriction: Clinical Characteristics and Placental Lesions and Possible Preventive Nutritional Targets.

BACKGROUND: The purpose of this study was to describe the placental lesions in pregnancies complicated by hypertensive disorders (HDP) and/or fetal growth restriction (FGR) and in uneventful control pregnancies. METHODS: This is a case control study that included singleton pregnancies with HDP and normally grown fetus (HDP-AGA fetus), with HDP and FGR, early FGR, late FGR, and uneventful pregnancies. Feto-placental Doppler velocimetry and sFlt-1/PlGF ratio were performed. Placental histology was evaluated blinded according to the Amsterdam Consensus criteria. RESULTS: Placental lesions with maternal vascular malperfusion (MVM) were significantly more frequent in HDP-FGR and early FGR (92% and 83%). MVM were significantly associated with abnormal feto-placental Doppler parameters, especially in early FGR. Delayed villous maturation (DVM) was associated with late FGR (83%). HDP-AGA fetus cases presented a heterogeneous pattern of placental lesions, including 60% of cases with MVM, but were not associated with abnormal Doppler feto-placental velocimetry. CONCLUSIONS: We found a prevalence of placental maternal vascular malperfusion in HDP-FGR and early FGR groups. These lesions were also associated with abnormal, anti-, and angiogenic markers. Conversely HDP-AGA fetus and late FGR presented more heterogeneous placental lesions not severe enough to cause feto-placental Doppler anomalies. These conditions are likely associated with different etiologies, such as maternal pre-pregnancy risk factors for metabolic syndrome. These findings suggest a possible preventive nutritional approach in addition to low-dose aspirin in pregnant women with predisposing factors for HDP-AGA fetuses and late FGR.

Second trimester uterine arteries pulsatility index is a function of placental pathology and provides insights on stillbirth aetiology: A multicenter matched case-control study.

INTRODUCTION: The aim of this study was to investigate the relationships between maternal vascular malperfusions (MVM) and second trimester uterine arteries pulsatility index (UtA-PI) in cases of stillbirth (SB), compared to live-birth (LB) matched controls. METHODS: This was a multicentre, observational, matched case-control study performed at five referral maternity centres over a 4-year period including SB and LB control pregnancies at high-risk for preeclampsia (PE) and/or fetal growth restriction (FGR), matched and stratified for UtA-PI MoM quartiles values of the SB cases. Logistic regression was used to assess the rates of each MVM finding, within each increasing MoM quartile subcategory in SB and matched LB controls. RESULTS: 82 SB and 82 LB matched high-risk pregnancies were included. Placental hypoplasia, placental infarction, retroplacental hematoma, distal villous hypoplasia and accelerated villous maturation showed a significant correlation with UtA-PI. At univariable analysis, placental infarction and distal villous hypoplasia were more highly associated with the increasing quartile uterine Doppler measurements (odds ratio 2.24 and 2.23, respectively). Logistic regressions showed a significant positive and independent association between rates of retroplacental hematoma or distal villous hypoplasia and stillbirth within corresponding UtA-PI MoM quartiles (odds ratio 5.21 and 2.28, respectively). DISCUSSION: We are providing evidence for characterization of two major etiological stillbirth categories, characterized by a positive or absent association with UtA-PI impairment and specific histopathological placental MVM lesions. Our results support a strict third trimester follow-up of cases with increased second trimester UtA-PI, in order to improve the reproductive chances of these pregnant patients.

Chronic deciduitis in stillbirths: are there any specific clinical associations?

INTRODUCTION: Placental chronic deciduitis is a lesion consistent with the presence of plasma cells within the placental basal plate. It could be associated with adverse pregnancy outcomes, including stillbirth. METHODS: We retrospectively evaluated a cohort of 180 antepartum stillborn cases from singleton pregnancies, with the aim of investigating the clinical-histopathological relationship. Placental slides were reviewed following the standard protocol proposed by the "Amsterdam consensus statement". RESULTS: We observed an association between chronic deciduitis and lesions consistent with maternal vascular malperfusion, delayed villous maturation, villitis of unknown etiology and maternal autoimmunity. CONCLUSIONS: The observed clinical-histopathological associations suggest that an extensive maternal investigation could improve the comprehension of factors interfering with the placental development and the increasing risk of adverse pregnancy outcomes. HighlightsChronic deciduitis is associated with lesions consistent with maternal vascular malperfusionChronic deciduitis is associated with delayed villous maturationChronic deciduitis is associated with villitis of unknown etiologyChronic deciduitis is associated with maternal autoimmunity.

Risk of stillbirth in older mothers: a specific delivery plan might be considered for prevention.

OBJECTIVE: In recent decades, the trend for women is to delay childbearing. However, worldwide, advanced maternal age is an independent risk factor for stillbirth, as well as advanced gestational age. National data are not available about stillbirths in the Italian population. We explored whether, at term of pregnancy, advanced maternal age is associated with an increased risk of stillbirth in Italy. We speculate that a policy of induction of labor at term of pregnancy in older mothers may significantly reduce the stillbirth. METHODS: Data provided by Italian Ministry of Health and National Statistical Institute were used to identify all singleton deliveries ≥22 weeks of gestation during a four years study period. We evaluated the outcome of pregnancy (livebirths or stillbirths) and we stratified data by gestational age and by maternal age at delivery. The hazard risk and the relative risk of stillbirth were calculated. RESULTS: The overall stillbirth rate was 3.4 per 1000, with a total of 6451 cases of stillbirths in the four years study period. Overall, the risk of stillbirth increases at term of pregnancy in all maternal age groups, especially in older mothers. A total of 674 stillbirths occurred in women aged 40 years or older and 24.2% of them (n = 163) occurred at term of pregnancy. Among women aged 40 years and above, 7.3% of stillbirths (49/674) occurred beyond 39 weeks of gestation. The hazard risk doubles from 39 to 40 weeks, from 0.60 per 1000 ongoing pregnancies to 1.16 per 1000 ongoing pregnancies; the relative risk at 40 weeks of gestation was the highest in the older mothers and was 5.17 (95% CI 3.16-8.46). CONCLUSIONS: The effect of maternal age on birth outcomes is a relevant aspect in Italy. If the association between maternal age and stillbirth is supposed to be part of the pathophysiology of fetal death, our data indicate that induction of labor before 40 weeks of gestation in women aged 40 years old or older might prevent overall 7.3% of stillbirths for induction at 39 weeks, 13% of stillbirths for induction at 38 weeks. To reduce potentially preventable stillbirths, caregivers should perform a specific risk assessment for each pregnant woman. The impact of maternal age should be seriously considered, and an individualized approach should be planned at term of pregnancy in older mothers, including the possibility of a slightly anticipation of induction of labor if spontaneously undelivered.

Meconium-stained amniotic fluid and histologic signs of fetal distress in stillbirths.

OBJECTIVE: Stillbirth is one of the most devastating adverse pregnancy outcome, but it is often associated with a missing post-mortem histological examination. We aimed at evaluating whether the staining of amniotic fluid reflects the fetal conditions surrounding the death and if it correlates with any histologic sign of fetal distress. STUDY DESIGN: Terminal gasping (represented by the massive presence of intra-alveolar squamous cells), thymic and adrenal cortex modifications were evaluated as histologic signs of fetal distress in stillbirths, and stratified according to the degree of staining of the amniotic fluid. RESULTS: The presence of meconium-stained amniotic fluid did not correlate with the presence of gasping and/or thymic and/or adrenal cortex changes. Clear amniotic fluid was not associated with the absence of histologic signs of distress. CONCLUSIONS: The evaluation of the staining of the amniotic fluid fails to identify distressed fetuses. A histologic evaluation of fetal organs provides detailed information, irrespective of the presence/absence of meconium-stained amniotic fluid.

Dynamic expression of NR2F1 and SOX2 in developing and adult human cortex: comparison with cortical malformations.

The neocortex, the most recently evolved brain region in mammals, is characterized by its unique areal and laminar organization. Distinct cortical layers and areas can be identified by the presence of graded expression of transcription factors and molecular determinants defining neuronal identity. However, little is known about the expression of key master genes orchestrating human cortical development. In this study, we explored the expression dynamics of NR2F1 and SOX2, key cortical genes whose mutations in human patients cause severe neurodevelopmental syndromes. We focused on physiological conditions, spanning from mid-late gestational ages to adulthood in unaffected specimens, but also investigated gene expression in a pathological context, a developmental cortical malformation termed focal cortical dysplasia (FCD). We found that NR2F1 follows an antero-dorsallow to postero-ventralhigh gradient as in the murine cortex, suggesting high evolutionary conservation. While SOX2 is mainly expressed in neural progenitors next to the ventricular surface, NR2F1 is found in both mitotic progenitors and post-mitotic neurons at GW18. Interestingly, both proteins are highly co-expressed in basal radial glia progenitors of the outer sub-ventricular zone (OSVZ), a proliferative region known to contribute to cortical expansion and complexity in humans. Later on, SOX2 becomes largely restricted to astrocytes and oligodendrocytes although it is also detected in scattered mature interneurons. Differently, NR2F1 maintains its distinct neuronal expression during the whole process of cortical development. Notably, we report here high levels of NR2F1 in dysmorphic neurons and NR2F1 and SOX2 in balloon cells of surgical samples from patients with FCD, suggesting their potential use in the histopathological characterization of this dysplasia.

Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome.

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

Comparison of treatments for the prevention of fetal growth restriction in obstetric antiphospholipid syndrome: a systematic review and network meta-analysis.

Women with criteria and non-criteria obstetric antiphospholipid syndrome (APS) carry an increased risk of pregnancy complications, including fetal growth restriction (FGR). The management of obstetric APS traditionally involves clinicians, obstetricians and gynaecologists; however, the most appropriate prophylactic treatment strategy for FGR prevention in APS is still debated. We performed a systematic review and network meta-analysis (NetMA) to summarize current evidence on pharmacological treatments for the prevention of FGR in APS. We searched PubMed and Embase from inception until July 2020, for randomized controlled trials and prospective studies on pregnant women with criteria or non-criteria obstetric APS. NetMA using a frequentist framework were conducted for the primary outcome (FGR) and for secondary outcomes (fetal or neonatal death and preterm birth). Adverse events were narratively summarised. Out of 1124 citations, we included eight studies on 395 pregnant patients with obstetric APS treated with low-dose aspirin (LDA) + unfractionated heparin (UFH) (n = 132 patients), LDA (n = 115), LDA + low molecular weight heparin (n = 100), LDA + corticosteroids (n = 29), LDA + UFH + intravenous immunoglobulin (n = 7), or untreated (n = 12). No difference among treatments emerged in terms of FGR prevention, but estimates were largely imprecise, and most studies were at high/unclear risk of bias. An increased risk of fetal or neonatal death was found for LDA monotherapy as compared to LDA + heparin, and for no treatment as compared to LDA + corticosteroids. The risk of preterm birth was higher for LDA + UFH + IVIg as compared to LDA or LDA + heparin, and for LDA + corticosteroids as compared to LDA or LDA + LMWH. No treatment was associated with an increased risk of bleeding, thrombocytopenia or osteopenia.

Pharmacological Interventions for the Prevention of Fetal Growth Restriction: A Systematic Review and Network Meta-Analysis.

The prevention of fetal growth restriction (FGR) is challenging in clinical practice. To date, no meta-analysis summarized evidence on the relative benefits and harms of pharmacological interventions for FGR prevention. We performed a systematic review and network meta-analysis (NetMA), searching PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception until November 2019. We included clinical trials and observational studies on singleton gestating women evaluating antiplatelet, anticoagulant, or other treatments, compared between each other or with controls (placebo or no treatment), and considering the pregnancy outcome FGR (primary outcome of the NetMA). Secondary efficacy outcomes included preterm birth, placental abruption, and fetal or neonatal death. Safety outcomes included bleeding and thrombocytopenia. Network meta-analyses using a frequentist framework were conducted to derive odds ratios (ORs) and 95% confidence intervals (CIs). Of 18,780 citations, we included 30 studies on 4,326 patients. Low molecular weight heparin (LMWH), alone or associated with low-dose aspirin (LDA), appeared more efficacious than controls in preventing FGR (OR 2.00, 95% CI 1.27-3.16 and OR 2.67, 95% CI 1.21-5.89 for controls vs. LMWH and LDA + LMWH, respectively). No difference between active treatments emerged in terms of FGR prevention, but estimates for treatments other than LMWH +/- LDA were imprecise. Only the confidence in the evidence regarding LMWH vs. controls was judged as moderate, according to the Confidence in Network Meta-Analysis framework. No treatment was associated with an increased risk of bleeding, although estimates were precise enough only for LMWH. These results should inform clinicians on the benefits of active pharmacological prophylaxis for FGR prevention.

The Burden of Placental Histopathology in Stillbirths Associated With Maternal Obesity.

OBJECTIVES: Obesity is an increasing health problem that has become a common medical disorder among women of childbearing age, representing worldwide a risk factor for stillbirth. The aim of the study is to evaluate the association between placental histopathologic findings and obesity in stillbirth. METHODS: Placentas were analyzed according to the Amsterdam consensus statement. Histologic findings in stillbirth from obese and lean mothers were analyzed and compared with those observed in liveborn controls. RESULTS: Stillbirth in obese mothers displayed placental pathology in all gestational ages, mostly at term of pregnancy. The most observed placental lesions were those consistent with maternal vascular malperfusion of the placental bed. Decidual arteriopathy and placental infarcts appeared specifically associated with maternal obesity. Moreover, obese women with stillbirth showed the highest cumulative number of placental lesions. CONCLUSIONS: Considering the significant association between stillbirth, maternal obesity, and placental histopathologic findings, health care providers should be aware about the importance of placental examination in obese women, especially in stillborn cases. The high prevalence of lesions consistent with vascular malperfusion of the placental bed suggests that stillbirth prevention strategies in obese women should rely on the development of tools to study and improve decidual artery functioning early in pregnancy.

Chromatinopathies: A focus on Cornelia de Lange syndrome.

In recent years, many genes have been associated with chromatinopathies classified as "Cornelia de Lange Syndrome-like." It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that "CdLS-like syndromes" are part of a larger "rare disease family" sharing multiple clinical features and common disrupted molecular pathways.

Dynamic acetylation profile during mammalian neurulation.

BACKGROUND: Neural tube defects (NTDs) result from failure of neural tube closure during embryogenesis. These severe birth defects of the central nervous system include anencephaly and spina bifida, and affect 0.5-2 per 1,000 pregnancies worldwide in humans. It has been demonstrated that acetylation plays a pivotal role during neural tube closure, as animal models for defective histone acetyltransferase proteins display NTDs. Acetylation represents an important component of the complex network of posttranslational regulatory interactions, suggesting a possible fundamental role during primary neurulation events. This study aimed to assess protein acetylation contribution to early patterning of the central nervous system both in human and murine specimens. METHODS: We used both human and mouse (Cited2 -/- ) samples to analyze the dynamic acetylation of proteins during embryo development through immunohistochemistry, western blot analysis and quantitative polymerase chain reaction. RESULTS: We report the dynamic profile of histone and protein acetylation status during neural tube closure. We also report a rescue effect in an animal model by chemical p53 inhibition. CONCLUSIONS: Our data suggest that the p53-acetylation equilibrium may play a role in primary neurulation in mammals.

Pharmacological interventions for the prevention of fetal growth restriction: protocol for a systematic review and network meta-analysis.

INTRODUCTION: Fetal growth restriction (FGR) includes different conditions in which a fetus fails to reach the own full growth, and accounts for 28%-45% of non-anomalous stillbirths. The management of FGR is based on the prolongation of pregnancy long enough for fetal organs to mature while preventing starvation. As for pharmacological management, most guidelines recommend treatment with low-dose aspirin and/or with heparin, although this approach is still controversial and innovative promising therapies are under investigation. As no firm evidence exists to guide clinicians towards the most effective therapeutic intervention, this protocol describes methods for a systematic review and network meta-analysis (NetMA) of pharmacological treatments for FGR prevention. METHODS AND ANALYSIS: We will search MEDLINE and Embase for clinical trials and observational studies performed on gestating women with clinically diagnosed risk of FGR. Experimental interventions will include heparin and low-molecular-weight heparin, acetylsalicylic acid, antiplatelet agents, phosphodiesterase type 3 and 5 inhibitors, maternal vascular endothelial growth factor gene therapy, nanoparticles, microRNA, statins, nitric oxide donors, hydrogen sulphide, proton pump inhibitors, melatonin, creatine and N-acetylcysteine, and insulin-like growth factors, compared between each other or to placebo or no treatment. Primary efficacy outcome is FGR. Secondary efficacy outcomes will be preterm birth, fetal or neonatal death and neonatal complications. For the safety outcome, all adverse events reported in included studies and experienced by either mothers, fetuses or newborns will be considered. Two review authors will independently screen title, abstract and full paper text, and will independently extract data from included studies. Where possible and appropriate, for primary and secondary efficacy outcomes, a NetMA will be performed using a random-effects model within a frequentist framework. Adverse events will be narratively described. ETHICS AND DISSEMINATION: Results will be disseminated through a peer-reviewed scientific journal, and by scientific congresses and meetings. PROSPERO REGISTRATION NUMBER: CRD42019122831.

Correction: Stillbirths at Term: Case Control Study of Risk Factors, Growth Status and Placental Histology.

[This corrects the article DOI: 10.1371/journal.pone.0166514.].

Fetal pancreatic Langerhans islets size in pregnancies with metabolic disorders.

Objective: Metabolic disorders are a pandemic and increasing health problem. Women of childbearing age may also be affected, thus an abnormal metabolism may interfere with pregnancy short- and long-term outcomes, harming both mother and child. In the context of an abnormal maternal and intrauterine metabolic milieu the development of fetal organs, including pancreas, may be affected. Aim: To investigate the effects of pregnancy metabolic disorders on the morphology of pancreatic Langerhans islets in human late-third trimester stillborn fetuses. Methods: Samples from fetal pancreas underwent a quantitative histological evaluation to detect differences between pregnancy with (cases, n = 9) or without (controls, n = 6) abnormal metabolism. Results: Results show that the islets size increases in fetuses from dysmetabolic pregnancies and that this increment is related to both beta-cell hyperplasia and hypertrophy. Moreover, according to pregnancy and fetal metabolic disorders, a threshold of abnormal size of the islets has been identified. Above this threshold the size of fetal pancreatic Langerhans islets should be considered excessively increased. Conclusion: The study suggests that an accurate fetal pancreas analysis supplies an important tool in stillborn fetus, to discover metabolic disturbances that should be kept in mind and managed in future pregnancies.

Antenatal Microbial Colonization of Mammalian Gut.

The widely accepted dogma of intrauterine sterility and initial colonization of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta, and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations and to assess fetal colonization before parturition. To this end, we analyzed sterilely collected intestinal tissues, placenta, and amniotic fluid from rodent fetuses and tissues from autoptic human fetuses. Total bacterial DNA was extracted from collected samples and analyzed by Next Generation Sequencing (NGS) techniques using hypervariable 16S ribosomal RNA (rRNA) regions (V3-V4). Colonizing microbes were visualized in situ, using labeled probes targeting 16S ribosomal DNA by fluorescent in situ hybridization. The NGS analysis showed the presence of pioneer microbes in both rat and human intestines as well as in rodent placentas and amniotic fluids. Microbial communities showed fetus- and dam-dependent clustering, confirming the high interindividual variability of commensal microbiota even in the antenatal period. Fluorescent in situ hybridization analysis confirmed the microbes' presence in the lumen of the developing gut. These findings suggest a possible antenatal colonization of the developing mammalian gut.

Overview on neural tube defects: From development to physical characteristics.

Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists.

The subthreshold micropulse laser treatment of the retina restores the oxidant/antioxidant balance and counteracts programmed forms of cell death in the mice eyes.

PURPOSE: Subthreshold micropulse laser (SMPL) has been increasingly used for the treatment of different retinal and choroidal macular disorders. However, the exact mechanisms of action have not yet been clearly defined. Therefore, we aimed to examine the role of SMPL treatment in the modulation of oxidant/antioxidant systems, apoptosis and autophagy in the mice eyes. METHODS: A specific laser contact lens for retina was positioned on the cornea of 40 mice (20 young and 20 old) in order to focus the laser on the eye fundus for SMPL treatment. Within 6 months, 20 animals received one treatment only, whereas the others were treated three times. Eye specimens underwent histological analysis and were used for thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) quantification, as well as for the superoxide dismutase 1 (SOD1) and the selenoprotein thioredoxin reductase 1 (TrxR1) expression evaluation. Western blot was performed for nitric oxide synthase (NOS) subtypes detection and to examine changes in apoptotic/autophagy proteins expression. RESULTS: SMPL treatment reduced TBARS and increased GSH and SOD1 in the mice eyes. It also reduced cytochrome c, caspase 3 expression and activity and cleaved caspase 9, and increased Beclin 1, p62 and LC3ß. The effects were more relevant in the elderly animals. CONCLUSION: Our results showed that SMPL therapy restored the oxidant/antioxidant balance within retinal layers and modulated programmed forms of cell death. Further studies may confirm these data and could evaluate their relevance in clinical practice.