Fetal Growth Restriction Research Articles

Transcerebellar diameter / abdominal circumference (TCD/AC) versus (HC/AC) head circumference / abdominal circumference --- USG prediction of fetal growth restriction? What do we observe in north Kerala, India

: Fetal growth restriction (FGR) refers to a condition in which a fetus is unable to achieve its genetically determined potential. A ratio of TCD /AC which is gestational age independent is very useful in predicting FGR. This prospective comparative study compared trans-cerebellar diameter / abdominal circumference versus head circumference / abdominal circumference in predicting fetal growth restriction. : A cross- sectional study done in 200 pregnant women attending Malabar Institute of Medical Sciences hospital during March 2018- May 2019. 40 pregnant women in third trimester with clinically suspected FGR over one year were the cases and 160 with normal growth pattern were the controls. Evaluation was done with 3.5 MHz frequency ultrasound. Fetal parameters such as BPD, HC, AC and FL were measured. Data were collected in Excel. Two morphometric ratios- TCD/AC and HC/AC will be calculated. Both TCD/ AC ratio and HC/AC of study group were compared with that of control group. The values above 2 standard deviations (SD) above mean were taken as FGR and was confirmed by postnatal newborn assessment by modified Ballard score. New born weight was compared with Fenton’s chart. If it was less than 10 percentile for the gestational age, it was diagnosed as a real case of FGR. Maximum number of cases (46.5%) belonged to the group 26-30 years. Around 23.5% in the group 31-35 years, 23% <= 25 years and 7% of the cases were >35 years. Clinical examination accounts for a sensitivity of 89.74%, Specificity of 96.9%, positive predictive value of 87.5% and negative predictive value of 97.5%. The sensitivity for TCD/ AC ratio is 94.87%. Specificity is 99.37%, positive predictive value is 97.36% and negative predictive value is 98.76%. TCD/AC and HC/AC were gestational age independent parameters and can be used in detecting IUGR with good diagnostic accuracy. However, TCD/AC ratio had a better diagnostic validity and accuracy compared to HC/AC ratio in predicting asymmetric FGR

Evaluation of fetal heart size, morphology and function with fetal growth restriction using fetal HQ.

Fetal growth restriction (FGR) is associated with various perinatal complications. Limited research has focused on the fetal heart in the context of FGR. This study aimed to investigate the application value of fetal heart quantification (HQ) technology in evaluating the size, morphology, and function of the heart in FGR. A total of 31 fetuses diagnosed with FGR in our hospital from April 2022 to May 2024 were included, alongside another 31 normal fetuses matched for gestational age as the control group. Ultrasound Doppler parameters of the middle cerebral artery (MCA), umbilical artery (UA), venous catheter, and fetal HQ parameters were collected for comparative analysis, and perinatal data were followed up. Fetuses with FGR exhibited significant differences in various parameters of the MCA and UA compared to the control group (P < 0.05). The four-chamber view end-diastolic transverse width, end-diastolic area, left ventricular (LV) end-diastolic area, end-systolic area, end-systolic length, end-diastolic volume, end-systolic volume, and right ventricular (RV) end-systolic area in the FGR group were significantly lower than those in the control group (P < 0.05). In the 24-segment analysis, the LV fractional shortening in the FGR group was greater than in the control group at segments 12 to 14, while the end-diastolic diameter (ED) at segments 5 to 13 of the LV and segments 1 to 14 of the RV were smaller than those in the control group, with statistical significance (P < 0.05). Analysis of each subgroup indicated that fractional shortening (FS) in the early-onset group was significantly greater than in the late-onset group at RV segments 2 to 8. LV-ED at segments 1 to 15 and RV-ED at segments 1 to 16 were significantly smaller in the early-onset group than in the control group, and LV ED segments 20 to 21 were significantly smaller in the early-onset group compared to the late-onset group (P < 0.05). FS in the mild group was significantly larger than in the normal group at LV segments 10 to 16. The severe group exhibited significantly smaller LV segment 2 to 11 ED and the mild group showed smaller RV segments 1 to 13 compared to the control group (P < 0.05). Fetal HQ is a promising technique for evaluating the cardiac function, size, and morphology in cases of FGR.

Intravoxel incoherent motion MRI to assess feto-placental diffusion and perfusion properties in small fetuses.

To investigate the use of intravoxel incoherent motion (IVIM) to study microperfusion and microstructural characteristics of lungs, brain, and placenta in normal and small fetuses. We retrospectively enrolled 30 small fetuses and 82 normal pregnancies who underwent a 1.5-T MRI examination using an IVIM-DWI. Small fetuses were distinguished in small for gestational age (SGA) and "true" fetal growth restriction (FGR). ROIs were placed on the brain parenchyma, lungs, and fetal/maternal placental sides. Differences in perfusion fraction f, diffusion coefficient D, and pseudo-diffusion coefficient D* and their correlation with gestational age (GA) and birth weight (BW) were investigated. LUNG: f showed significantly lower values (p = 2·10-7) in small fetuses (SGA + FGR); f discriminates SGA and FGR from normal (p = 0.001; p = 1·10-6). f increases with GA (p < 0.0001) in the control group; a positive correlation was also obtained in small fetuses, although less significant. FGR showed lower f values than normal ones, in both the fetal (p = 1.4·10-7) and maternal side (p = 0.001); f discriminates between SGA and FGR (p = 0.03). In small fetuses (SGA + FGR), f correlates positively with BW. D values in supratentorial white matter (WM) were significantly higher compared to other regions, in both normal and small fetuses. Small fetuses showed higher D values in occipital WM and pons (p = 0.041; p = 0.027) than in normal. D correlates negatively with GA in the healthy group. No correlation between D and GA was found in SGA + FGR group. In our study, IVIM-MRI allowed us to detect microstructural and microperfusion changes in the placenta, brain, and lung of small fetuses, noninvasively.

Irisin Improves Preeclampsia by Promoting Embryo Implantation and Vascular Remodeling.

Preeclampsia is a pregnancy-specific disorder with unclear pathogenesis. Irisin, a recently identified exercise-induced factor, significantly influences lipid metabolism and cardiovascular function. Nonetheless, its role in trophoblast development during human placentation and the related intracellular signaling pathways remain poorly understood. We assessed peripheral blood irisin expression in early pregnancy among patients with preeclampsia and its correlation with key clinical indicators. In trophoblast cell lines and mice, we used exogenous irisin and viral knockdown to investigate functional changes. Phosphorylation-specific antibody arrays and dual-luciferase reporter assays were used to explore downstream molecular mechanisms, which were subsequently validated in trophoblast cell lines and relevant gene knockout mice. In early pregnancy, patients with preeclampsia exhibit decreased peripheral blood irisin levels, occurring earlier than traditional predictive markers, such as PLGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1). Furthermore, irisin concentration is positively correlated with proteinuria and abnormal blood pressure during pregnancy. Exogenous irisin significantly enhanced trophoblast cell migration, invasion, and proliferation while inhibiting apoptosis. It also increased STAT (signal transducers and activators of transcription) 4 phosphorylation and its binding to the GLUT (glucose transporter)-3 promoter, resulting in elevated GLUT-3 expression and glucose uptake in trophoblast cells. In vivo, increased peripheral irisin promoted embryo implantation, vascular remodeling, and enhanced glucose uptake, whereas reduced irisin resulted in a preeclampsia-like phenotype characterized by elevated blood pressure, proteinuria, renal-placental dysfunction, adipose accumulation, and restricted fetal growth. Peripheral irisin improves preeclampsia by promoting embryo implantation and vascular remodeling through the activation of the STAT4/GLUT-3 pathway. Reduced peripheral irisin may contribute to preeclampsia-like pathologies. This study supports the advocacy for appropriate exercise during early pregnancy and provides new insights for preeclampsia prevention.

An Association Between Fetal Subarachnoid Space and Various Pathologies Using MR Imaging

Background/Objectives: This study aimed to explore a relationship between the fetal subarachnoid space (SAS) width and various fetal pathologies, employing fetal brain MRI scans. Methods: A retrospective collection of fetal brain MRI scans of 78 fetuses was performed with sonographic indications of microcephaly, macrocephaly, or fetal growth restriction (FGR), during a 7-year period at a single tertiary center. The SAS width (named the SAS index) was manually measured in millimeters in ten specific anatomical locations (four in the axial plane and six in the coronal plane), and then converted to centiles by comparing it to (previously collected) data of apparently healthy fetuses. We evaluated the median SAS centiles using the Kruskal–Wallis and Mann–Whitney U tests for statistical comparison. Results: Seventy-eight subjects (mean gestational age of MRI scan 34.2 ± 2.2 weeks) were evaluated. The median SAS centiles were consistently higher in the macrocephaly group compared to the microcephaly group in all ten anatomical locations (statistically significant except coronal left inferior temporal gyri). Most pronounced difference was displayed in the insula gyri (axial and coronal). The median SAS centiles were higher in the microcephaly group when compared with FGR across all ten anatomical locations (all were statistically significant except for coronal frontal and insula gyri), and the maximal difference was found in the frontal gyri of both planes. The median SAS indexes (IQR) of the three groups in millimeters: macrocephaly 91.55 (86.35–101.05), microcephaly 59.46 (50.00–66.91), and FGR 53.21 (49.71–59.10), p &lt; 0.001. Conclusions: We found a statistically significant association between the fetal subarachnoid space and various fetal pathologies: macrocephaly, microcephaly, and FGR.

Abstract 4121970: Early to Mid-Gestational Testosterone Excess Sex-specifically Reprograms Cardiac Transcriptome and Metabolome Profiles of Sheep Fetuses

Exposure of sheep to excess testosterone (T) from days 30-90 of gestation (term 147 days) perturbs maternal systemic lipidome in late gestation, induces fetal growth restriction and sexually dimorphic perturbation in the cardiac left ventricular (LV) transcriptome in gestational (GD) day 90 fetuses culminating in cardiometabolic dysfunction in adult female offspring. We hypothesized that the detrimental impact of prenatal T excess on fetal cardiac transcriptome is a programmed event that will persist even after cessation of excess T exposure and will be accompanied by changes in fetal metabolome. Pregnant ewes were injected with 100 mg intramuscular T propionate or vehicle (C), twice weekly from GD 30-90. On GD120±5, 30 days after cessation of T treatment fetal weights were recorded, left ventricle (LV) tissue and fetal plasma processed for transcriptomics by RNA sequencing and metabolomics analysis (Female C (FC) n=6, T (FT) n=7; Male C (MC) n=6, T (MT) n=7). LV transcriptome-based pathways enrichment analysis revealed 1) downregulation of pathways associated with oxidative phosphorylation, citric acid cycle, pyruvate metabolism; 2) upregulation of TGF-β signaling pathway in T fetuses compared to C (p&lt;0.05, FDR&lt;0.1); 3) selective downregulation of the glycolytic pathway in MT relative to MC as opposed to downregulation of mitochondria-related pathways in FT vs FC (p&lt;0.05, FDR&lt;0.1). LV lipidomics analyses found glycerophospholipids and sphingolipids as main class lipid metabolites to be enriched in FT relative to FC fetuses (p&lt;0.05, ER&gt;1). Fetal systemic lipidome main class metabolites enriched (p&lt;0.05, ER&gt;2) in T vs C fetuses included 1) sphingomyelins in both sexes 2) fatty acyls metabolites only in MT vs MC as opposed to glycerophospholipids only in FT vs FC. LV polar metabolites enriched (p&lt;0.05, ER&gt;2) included 1) arginine&amp;proline metabolism pathways in T vs C in both sexes 2) nicotinate and nicotinamide metabolism only in MT vs MC (p&lt;0.05, ER&gt;3), and porphyrin, riboflavin metabolism and N-glycan biosynthesis pathways only in FT vs FC. Systemic polar metabolites enriched (p&lt;0.05, ER&gt;2) included 1) D-amino acid metabolism pathways in T vs. C, 2) valine, leucine, and isoleucine pathways only in FT vs FC and glycerophospholipid and sphingolipid metabolism only in MT vs MC. These results suggest persistence of sex-specific perturbation in fetal transcriptome and systemic and cardiac metabolome in late gestational fetuses exposed to prenatal T excess.

Artificial Ex Utero Systems to Treat Severe Periviable Fetal Growth Restriction—A Possible Future Indication?

Fetal growth restriction, or intrauterine growth restriction, is a common gestational condition characterized by reduced intrauterine growth. However, severe periviable fetal growth restriction is still associated with elevated perinatal mortality and morbidity. The current literature advises delivery once it is deemed that fetal compromise is evident. As uteroplacental insufficiency is the most common etiology of this condition, we hypothesize that the use of artificial ex utero systems to provide adequate nutrition and recreate the uterine environment may be a viable treatment option in this situation, even with the possibility of treating severe fetal growth restriction and prevent sequelae. There are promising experimental studies in sheep models investigating the artificial ex utero system for potential prenatal conditions, but future additional investigation is needed before translating to clinical trials in humans.

Metabolomic signatures associated with fetal growth restriction and small for gestational age: a systematic review.

The pathways involved in the pathophysiology of fetal growth restriction (FGR) and small for gestational age (SGA) are incompletely understood. We conduct a systematic review to identify metabolomic signatures in maternal and newborn tissues and body fluids samples associated with FGR/SGA. Here, we report that 825 non-duplicated metabolites were significantly altered across the 48 included studies using 10 different human biological samples, of which only 56 (17 amino acids, 12 acylcarnitines, 11 glycerophosphocholines, six fatty acids, two hydroxy acids, and eight other metabolites) were significantly and consistently up- or down-regulated in more than one study. Three amino acid metabolism-related pathways and one related with lipid metabolism are significantly associated with FGR and/or SGA: biosynthesis of unsaturated fatty acids in umbilical cord blood, and phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, and phenylalanine metabolism in newborn dried blood spot. Significantly enriched metabolic pathways were not identified in the remaining biological samples. Whether these metabolites are in the causal pathways or are biomarkers of fetal nutritional deficiency needs to be explored in large, well-phenotyped cohorts.

Evaluation of pitolisant, sodium oxybate, solriamfetol, and modafinil for the management of narcolepsy: a retrospective analysis of the FAERS database

ObjectiveNarcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy.MethodsFive-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals.ResultsAfter data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse.ConclusionThe majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy.

Assessment of the development of the central nervous system in fetuses with fetal growth restriction.

To evaluate the development of the central nervous system in fetuses with fetal Growth Restriction. A total of 146 pregnant women who underwent prenatal ultrasonography in Cangzhou People's Hospital from January 2022 to May 2024 were selected, all with singleton pregnancies. Among them, 73 fetuses were in the fetal growth restriction group, with ages ranging from 20 to 33 + 6weeks. The indicators for evaluating the cerebral sulci included the depth and angle of the parietooccipital sulci, the width and depth of the sylvian fissure, the width of the uncovered insula, uncover insular ratio, the depth of the calcarine sulci, and the head circumference. The hemodynamic indicators comprised the ratio of the umbilical artery resistance index, the umbilical artery pulse index, the middle cerebral artery resistance index, the middle cerebral artery pulse index, and the cerebral placental blood flow pulse index. The above parameters were analyzed statistically. In this study, the depth of the parietooccipital sulci, the depth of the calcarine sulci, and the width of the sylvian fissure were smaller in the fetal growth restriction group than those in the control group, and the angle of the parietooccipital sulci and the width of the uncovered insula were larger than those in the control group (all P < 0.05). The fetal middle cerebral artery resistance index, middle cerebral artery pulsation index and cerebroplacental pulsation ratio in the FGR group were lower than those in the control group (all P < 0.05). The development of the cerebral cortex in FGR fetuses is slower than that in normal fetuses, and the alteration of fetal hemodynamics might be one of the reasons for the delayed development of the cerebral cortex in FGR fetuses.

Alterations in maternal–fetal gut and amniotic fluid microbiota associated with fetal growth restriction

BackgroundFetal growth restriction (FGR) is typically characterised as the fetus’ inability to reach its inherent growth potential. A growing body of evidence points to the important role of the maternal gut microbiota in FGR development. However, comprehensive research on changes in maternal–fetal gut and intrauterine microbiota related to FGR is lacking.MethodsIn this case–control study, we sequenced bacterial 16S rRNA from 35 maternal faecal, 35 meconium, and 31 amniotic fluid samples collected from 19 pregnant women diagnosed with FGR and 16 healthy controls. We identified putative bacterial taxonomic and functional characteristics associated with FGR by comparing these to control samples.ResultsWe identified 34 differential operational taxonomic units (OTUs) in amniotic fluid, seven differential OTUs in maternal faecal matter, and two differential OTUs in meconium. Compared to controls, FGR subjects exhibited enriched bacterial OTUs of the genus Bacteroides in the maternal gut. They also had depleted OTUs of the order Enterobacterales and genus Pseudomonas in the amniotic fluid and genus Stenotrophomonas in the fetal gut. These altered bacterial OTUs showed a significant correlation with neonatal weight and fetal ultrasonographic indexes. Additionally, we identified differential microbial functional pathways related to glycan and lipid metabolism in the maternal gut. We developed diagnostic biomarkers for FGR based on the maternal–fetal gut and amniotic fluid microbiota.ConclusionsThis study offers a comprehensive overview of the shifts in microbial composition and functional pathways in the maternal–fetal gut and amniotic fluid microbiota related to FGR, and present novel insights into the development and screening of FGR. However, the assessment of contamination’s impact on meconium and amniotic fluid remains inconclusive, necessitating further rigorous experimentation to address this scientific inquiry in future studies.

Systematic Review of Obstetric and Child Outcomes of Prenatal Exposure to Inhalants in the Context of a Use Disorder.

Inhalants are often used for their psychoactive effects, producing feelings of euphoria. Inhalant and solvent use is a serious public health concern, yet little is known about their effects on perinatal, fetal, and child outcomes. The aim of our review is to evaluate the impact of inhalant use by pregnant people on maternal, fetal, neonatal, and early childhood outcomes. A systematic review was conducted on March 1, 2023, in 6 databases using relevant keywords. Bias assessment was performed using JBI Critical Appraisal Tools. Studies were included if they described a prenatal exposure to an inhalant; focused on maternal, fetal, neonatal, or early childhood outcomes; and were published as peer-reviewed reports in English. The search yielded 1101 unique references with 22 studies meeting eligibility criteria and representing 205 pregnancies and 171 infants.The most common symptom of inhalant use reported in pregnant people was altered mentation, followed by renal tubular acidosis (RTA) reported with toluene use. Most common fetal outcomes included fetal growth restriction and preterm delivery (<37 weeks), while neonatal outcomes were withdrawal symptoms, such as jitteriness, trouble feeding, and dystonia. Child outcomes included developmental delays, including cognitive and speech impairments, and postnatal growth restriction, including microcephaly. Perinatal, fetal, and child outcomes associated with inhalant use among pregnant individuals are largely based on case reports and series. Prospective studies are needed to better characterize these outcomes, reduce stigma, increase equitable access to treatment, and identify potential interventions to reduce use and potential harm.

The role and research progress of gut microbiota in placenta-derived diseases

Gut microbiota plays an important role in maintaining the normal function of intestinal tract, regulating the body's immunity, metabolism and other physiological processes. In recent years, the theory that gut microbiota dysbiosis affects the disease occurrence of various organ systems through the gut-organ axis has been gradually confirmed. Placental diseases of pregnancy includes early onset preeclampsia, fetal growth restriction, etc., the pathogenesis of which is unclear, but can cause adverse pregnancy outcomes. Researches show that gut microbiota dysbiosis has a certain correlation with the occurrence of placental diseases, and its mechanism may affect the occurrence of placental diseases by regulating systemic and local placental metabolism, inflammatory response and immune response. This article reviews the research progress on the effects of maternal gut microbiota dysbiosis on the occurrence of placenta-derived diseases, and provides clues for exploring the application of gut microecology to the prevention and treatment of placenta-derived diseases.

Extracellular Vesicles as Biomarkers of Pregnancy Complications

Extracellular vesicles (EVs) are double-membrane vesicles that facilitate intercellular communication and play a pivotal role in both physiological and pathological processes. A substantial body of evidence suggests that EVs play a role in the pathogenesis of various pregnancy complications. Because EVs can be detected in the peripheral blood, they are potential biomarkers for the early diagnosis of pregnancy complications and foetal developmental disorders. The majority of studies have demonstrated a correlation between alterations in the concentration of EVs and changes in their contents and the occurrence of pregnancy complications. Despite the current limitations in establishing a clear link between these findings and the pathogenesis of the disease, as well as the lack of sufficient evidence to support their use in clinical practice, it is noteworthy to highlight the potential role of specific miRNAs carried by EVs in the development of pregnancy complications. These include miR-210 and miR-136-5p for pre-eclampsia and gestational diabetes mellitus, miR-155, miR-26b-5p, miR-181a-5p, miR-495 and miR-374c for pre-eclampsia and preterm birth. The following miRNAs have been identified as potential biomarkers for preterm birth and gestational diabetes mellitus: miR-197-3p and miR-520h, miR-1323, miR-342-3p, miR-132-3p, miR-182-3p, miR-517-3p, miR-222-3p, miR-16-5p and miR-126-3p. Additionally, miR-127-3p has been linked to foetal growth restriction and preterm birth. Nevertheless, it would be premature to propose that EVs can be employed as biomarkers for pregnancy complications. Further research and the accumulation of results obtained using the methods proposed in the MISEV2023 guidelines will enable a definitive conclusion to be reached.

Hypospadias Associated With Fetal Growth Restriction: A Multicentric Descriptive and Prognostic Cohort Study.

To determine the prevalence of genetic and endocrine abnormalities and to assess fetal, neonatal and surgical outcomes in cases of hypospadias associated with fetal growth restriction. A multicentric retrospective study was conducted across five prenatal diagnosis centers in Paris. The cohort encompassed all fetuses diagnosed with the combination of fetal growth restriction < 10th percentile (FGR) and hypospadias from 2013 to 2021. Maternal data, fetal outcome and results of prenatal investigations were collected, along with postnatal data, encompassing endocrinological and genetic assessments, functional aspects and surgical outcomes. Among the 82 patients included in the cohort, there were 14 (17%) terminations of pregnancy and four (5%) in utero deaths, leaving 64 (78%) live neonates, including five (6%) with early neonatal death. Among the 52 (63%) cases where hypospadias and FGR were considered as ultrasound-isolated anomalies, six (12%, [3.2%-20.8%]) exhibited chromosomic, genetic, or endocrinological abnormalities diagnosed half prenatally and half postnatally. Fifty percent of the overall hypospadias were proximal. Most children underwent surgical intervention before reaching 2years of age, with 50% encountering complications and often required reintervention. The association of FGR and hypospadias should not be underestimated as genetic or endocrinological abnormalities were identified even when hypospadias and FGR initially appear isolated. Additionally, the overall prognosis may be worsened using complex and iterative surgical procedures.

Low PAPPA and Its Association with Adverse Pregnancy Outcomes in Twin Pregnancies: A Systematic Review of the Literature and Meta-Analysis

Background: It is well established in the literature that pregnancy-associated plasma protein-A (PAPP-A) is linked to several adverse pregnancy outcomes, including pre-eclampsia (PE), fetal growth restriction (FGR), and preterm birth (PTB) in singleton pregnancies. However, data regarding such an association in twin pregnancies are lacking. The primary goal of this systematic review and meta-analysis was to assess the potential value of low PAPP-A levels in the prediction of the subsequent development of hypertensive disorders of pregnancy (HDPs), PTB, and small for gestational age (SGA)/FGR fetuses in twin pregnancies and investigate its association with the development of gestational diabetes, intrauterine death (IUD) of at least one twin, and birth weight discordance (BWD) among the fetuses. Methods: Medline, Scopus, CENTRAL, Clinicaltrials.gov, and Google Scholar databases were systematically searched from inception until 31 July 2024. All observational studies reporting low PAPP-A levels after the performance of the first-trimester combined test as part of the screening for chromosomal abnormalities with reported adverse pregnancy outcomes were included. Results: The current systematic review encompassed a total of 11 studies (among which 6 were included in the current meta-analysis) that enrolled a total of 3741 patients. Low PAPP-A levels were not associated with HDPs (OR 1.25, 95% CI 0.78, 2.02, I-square test: 13%). Low PAPP-A levels were positively associated with both the development of preterm birth prior to 32 (OR 2.85, 95% CI 1.70, 4.77, I-square test: 0%) and 34 weeks of gestational age (OR 2.09, 95% CI 1.34, 3.28, I-square test: 0%). Furthermore, low PAPP-A levels were positively associated with SGA/FGR (OR 1.58, 95% CI 1.04, 2.41, I-square test: 0%). Prediction intervals indicated that the sample size that was used did not suffice to support these findings in future studies. Conclusions: Our study indicated that low PAPP-A levels are correlated with an increased incidence of adverse perinatal outcomes in twin pregnancies. Identifying women at elevated risk for such adversities in twin pregnancies may facilitate appropriate management and potential interventions, but additional studies are required to identify the underlying mechanism linking PAPP-A with those obstetrical complications.

Insight into the post-translational modifications in pregnancy and related complications.

Successful pregnancy is dependent on a number of essential events, including embryo implantation, decidualization and placentation. Failure of the above process may lead to pregnancy-related complications, including preeclampsia (PE), gestational diabetes mellitus (GDM), preterm birth, fetal growth restriction (FGR), etc., may affect 15% of pregnancies, and lead to increased mortality and morbidity of pregnant women and perinatal infants, as well as the occurrence of short-term and long-term diseases. These complications have distinct etiology and pathogenesis, and the present comprehension is still lacking. Post-translational modifications (PTMs) are important events in epigenetics, altering the properties of proteins through protein hydrolysis or the addition of modification groups to one or more amino acids, with different modification states regulating subcellular localization, protein degradation, protein-protein interaction, signal transduction and gene transcription. In this review, we focus on the impact of various PTMs on the progress of embryo and placenta development and pregnancy-related complications, which will provide important experimental bases for exploring new insights into the physiology of pregnancy and pathogenesis associated with pregnancy complications.

Placental gene therapy in nonhuman primates: a pilot study of maternal, placental, and fetal response to non-viral, polymeric nanoparticle delivery of IGF1.

Currently, there are no placenta-targeted treatments to alter the in utero environment for administration to pregnant women who receive a diagnosis of fetal growth restriction (FGR). Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like growth factor 1 (IGF1) transgene to correct placental insufficiency in small animal models of FGR. Our goals were to extend these studies to a proof-of-concept study in the pregnant macaque, establish feasibility of nanoparticle-mediated gene therapy delivery to trophoblasts, and investigate the acute maternal, placental, and fetal responses to treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles (GFP- or IGF1-expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h (GFP; n = 1), 48 h (IGF1; n = 3) or 10 days (IGF1; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4), and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using Western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transient transgene expression in villous syncytiotrophoblast. No off-target expression was observed in either maternal or fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4, and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 days after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent overactivity in the normal pregnancy environment. The lack of adverse maternal reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis, indicates no deleterious impact of treatment during the acute phase of study.

Kidney disease and reproductive health.

Understanding the relationship between reproductive health and kidney function is important to provide holistic care for people living with kidney disease. Chronic kidney disease (CKD) has negative impacts on both male and female fertility owing to factors including inflammation, hormonal dysregulation, reduced ovarian reserve, reduced sperm quality and sexual dysfunction. However, pregnancy is achievable for most cisgender women with kidney disease, including kidney transplant recipients and patients on dialysis. CKD in pregnancy is associated with health risks to the mother and child, including increased risk of progression of kidney disease, hypertensive complications of pregnancy, and neonatal complications including fetal growth restriction, preterm birth and stillbirth. However, with appropriate pre-pregnancy counselling, fertility assessment and support, health optimization, and evidence-based antenatal care, the majority of patients will achieve a good outcome. Medication safety should be reviewed before and during pregnancy and lactation, weighing the risk of disease flare against potential adverse effects on the offspring. Important areas for further research include the optimal timing of delivery and the short- and long-term cardiovascular and renal impacts of pregnancy in patients with CKD, as well as long-term kidney and cardiovascular outcomes in their offspring.

Fetal growth ultrasound in obese patients for the detection of growth abnormalities.

To examine the impact of maternal obesity on fetal growth abnormalities including fetal growth restriction (FGR) and large for gestational age (LGA) fetuses. Secondary analysis from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). The study excluded individuals with pregestational or gestational diabetes, chronic hypertension, and other major maternal medical conditions. Ultrasound assessments were performed at 16 - 21 and 22 - 29 weeks of gestation. Our exposure was the presence of pre-pregnancy obesity. Our primary outcome was rates of fetal growth abnormalities identified by ultrasound, defined as FGR (estimated fetal weight [EFW] or abdominal circumference < 10th percentile) or LGA (EFW > 90 th percentile) among obese compared to non-obese women. A secondary analysis was performed after limiting ultrasound performed from 28-29 weeks. To estimate adjusted relative risks (aRR) with 95% confidence intervals (95%CIs), we used generalized linear models with Poisson distribution and log link using robust error variance, adjusting for the predefined covariates. Of 7,354 participants, 1,443 (19.6%) had pre-pregnancy obesity while 5,911 (80.4%) did not. Pre-pregnancy obesity compared with normal weight was associated with an increased risk of fetal growth abnormalities both at 16-21 weeks (16.0% vs. 13.2%; aRR 1.23; 95%CI 1.06-1.42) and 22-29 weeks (16.0% vs. 12.1%; aRR 1.33; 95%CI 1.14-1.54). Furthermore, pre-pregnancy obesity compared with normal weight was associated with an increased risk of LGA both at 16-21 weeks (12.5% vs. 10.3%; aRR 1.24; 95%CI 1.05-1.47) and 22-29 weeks (10.6% vs. 6.9%; aRR 1.66; 95%CI 1.38-2.01). In a secondary analysis limited to the ultrasound 28-29 weeks, both fetal growth abnormalities and LGA were associated with the presence of obesity. In any of the analyses, pre-pregnancy obesity was not associated with FGR compared to normal weight. Maternal obesity is associated with an increased risk of fetal growth abnormalities and LGA fetuses.