Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.

Gestational organophosphate esters (OPEs) exposure in association with placental DNA methylation levels of peroxisome proliferator-activated receptors (PPARs) signaling pathway-related genes.

BACKGROUND: Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. OBJECTIVES: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth. METHODS: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth. RESULTS: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation. CONCLUSIONS: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.

Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways.

Maternal Zika virus (ZIKV) infection during pregnancy has been associated with severe intrauterine growth restriction (IUGR), placental damage, metabolism disturbances, and newborn neurological abnormalities. Here, we investigated the impact of maternal ZIKV infection on placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) or High (5 × 107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, and tissue was collected at GD18.5 (term). Fetal-placental growth was impaired in male fetuses, which exhibited higher placental expression of the ZIKV infective marker, eukaryotic translation initiation factor 2 (eIF2α), but lower levels of phospho-eIF2α. There were no differences in fetal-placental growth in female fetuses, which exhibited no significant alterations in placental ZIKV infective markers. Furthermore, ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentae, with no differences in amino acid transport potential. In contrast, ZIKV did not impact glucose transporters in male placentae but downregulated sodium-coupled neutral amino acid 2 (Snat2) transporter expression. We also observed sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV-infected pregnancies, showing that ZIKV can disturb placental nutrient sensing. Our findings highlight molecular alterations in the placenta caused by maternal ZIKV infection, shedding light on nutrient transport, sensing, and availability. Our results also suggest that female and male placentae employ distinct coping mechanisms in response to ZIKV-induced metabolic changes, providing insights into therapeutic approaches for congenital Zika syndrome.

Prenatal diagnosis of SLC25A24 Fontaine progeroid syndrome: description of the fetal phenotype, genotype and detection of parental mosaicism.

BACKGROUND: Fontaine progeroid syndrome (FPS, OMIM 612289) is a recently identified genetic disorder stemming from pathogenic variants in the SLC25A24 gene, encoding a mitochondrial carrier protein. It encompasses Gorlin-Chaudry-Moss syndrome and Fontaine-Farriaux syndrome, primarily manifesting as craniosynostosis with brachycephaly, distinctive dysmorphic facial features, hypertrichosis, severe prenatal and postnatal growth restriction, limb shortening, and early aging with characteristic skin changes, phalangeal anomalies, and genital malformations. CASES: All known occurrences of FPS have been postnatally observed until now. Here, we present the first two prenatal cases identified during the second trimester of pregnancy. While affirming the presence of most postnatal abnormalities in prenatal cases, we note the absence of a progeroid appearance in young fetuses. Notably, our reports introduce new phenotypic features like encephalocele and nephromegaly, which were previously unseen postnatally. Moreover, paternal SLC25A24 mosaicism was detected in one case. CONCLUSIONS: We present the initial two fetal instances of FPS, complemented by thorough phenotypic and genetic assessments. Our findings expand the phenotypical spectrum of FPS, unveiling new fetal phenotypic characteristics. Furthermore, one case underscores a potential novel inheritance pattern in this disorder. Lastly, our observations emphasize the efficacy of exome/genome sequencing in both prenatal and postmortem diagnosis of rare polymalformative syndromes with a normal karyotype and array-based comparative genomic hybridization (CGH).

Association between risk of infant death and birth-weight z scores according to gestational age: A nationwide study using the Finnish Medical Birth Register.

OBJECTIVE: To investigate the association between infant mortality and birth weight using estimated fetal weight (EFW) versus birth-weight charts, by gestational age (GA). METHODS: This nationwide population-based study used data from the Finnish Medical Birth Register from 2006 to 2016 on non-malformed singleton live births at 24-41+6 weeks of gestation (N = 563 630). The outcome was death in the first year of life. Mortality risks by birth-weight z score, defined as a continuous variable using Marsál's EFW and Sankilampi's birth-weight charts, were assessed using generalized additive models by GA (24-27+6, 28-31+6, 32-36+6, 37-38+6, 39-41+6 weeks). We calculated z score thresholds associated with a two- and three-fold increased risk of infant death compared with newborns with a birth weight between 0 and 0.675 standard deviations. RESULTS: The z score thresholds (with corresponding centiles in parentheses) associated with a two-fold increase in infant mortality were: -3.43 (<0.1) at 24-27+6 weeks, -3.46 (<0.1) at 28-31+6 weeks, -1.29 (9.9) at 32-36+6 weeks, -1.18 (11.9) at 37-38+6 weeks, and - 1.34 (9.0) at 39-41+6 weeks according to the EFW chart. These values were - 2.43 (0.8), -2.62 (0.4), -1.34 (9.0), -1.37 (8.5), and - 1.43 (7.6) according to the birth-weight chart. CONCLUSION: The association between birth weight and infant mortality varies by GA whichever chart is used, suggesting that different thresholds for the screening of growth anomalies could be used across GA to identify high-risk newborns.

Gestational exposure to organochlorine compounds and metals and infant birth weight: effect modification by maternal hardships.

BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Effects of antenatal corticosteroids on fetal hemodynamics: a longitudinal study.

Objective: To study the effect of antenatal corticosteroid administration on fetal hemodynamics using longitudinal analysis of Doppler waveforms in the umbilical artery (UA) and middle cerebral artery (MCA). Materials and Methods: This was a retrospective study that included 30 fetuses at risk for preterm birth. Twenty-eight pregnant women were treated with betamethasone for fetal lung maturation. Doppler examinations of the UA and MCA were performed once before and three or eight times after corticosteroid administration. We used a Bayesian hierarchical linear model. Reference ranges were constructed, and associations between variables (gestational age and pre-eclampsia) were tested. Results: The mean maternal age, gestational age at betamethasone administration, and gestational age at delivery were 32.6 ± 5.89 years, 30.2 ± 2.59 weeks, and 32.9 ± 3.42 weeks, respectively. On UA Doppler, there was a significant decrease in the pulsatility index (PI) after corticosteroid administration, with a mean of 0.1147 (credibility interval: 0.03687-0.191) in three observations and a median of 0.1437 (credibility interval: 0.02509-0.2627) in eight observations. However, there was no significant change in the Doppler MCA PI, regardless of gestational age and the presence or absence of pre-eclampsia. Conclusion: Although antenatal corticosteroid administration induced a significant decrease in the Doppler UA PI, we observed no change in the cerebral vasculature.

Objetivo: Estudar o efeito da administração antenatal de corticosteroides na hemodinâmica fetal mediante análise longitudinal do Doppler na artéria umbilical (AU) e artéria cerebral média (ACM). Materiais e Métodos: Este foi um estudo retrospectivo que incluiu 30 fetos com risco de nascimento pré-termo. Vinte e oito gestantes foram tratadas com betametasona para maturação pulmonar fetal. Os exames de Doppler da AU e da ACM foram realizados uma vez antes e depois da administração de corticosteroides, num total de três ou oito observações. Utilizamos o modelo linear hierárquico com abordagem Bayesiana. Foram construídos os intervalos de referência e testadas associações entre variáveis (idade gestacional e pré-eclâmpsia). Resultados: A média ± desvio-padrão da idade materna, idade gestacional na administração de betametasona e idade gestacional no parto foram 32,6 ± 5,89 anos, 30,2 ± 2,59 semanas e 32,9 ± 3,42 semanas, respectivamente. No Doppler da AU, verificou-se diminuição significativa do índice de pulsatilidade (IP) com a terapêutica com corticosteroides (média: 0,1147 [0,03687-0,191]; em três observações) (mediana: 0,1437 [0,02509-0,2627]; em oito observações). No entanto, não foi observada alteração significativa no IP do Doppler da ACM, independentemente da idade gestacional e do diagnóstico de pré-eclâmpsia. Conclusão: Os corticosteroides pré-natais induziram diminuição significativa no IP do Doppler da AU, mas não houve alteração na vasculatura cerebral.

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

The search for blood biomarkers that indicate risk of adverse neurodevelopmental outcomes in fetal growth restriction.

Fetal growth restriction (FGR) impacts 5%-10% of pregnancies and is associated with increased risk of mortality and morbidity. Although adverse neurodevelopmental outcomes are observed in up to 50% of FGR infants, a diagnosis of FGR does not indicate the level of risk for an individual infant and these infants are not routinely followed up to assess neurodevelopmental outcomes. Identifying FGR infants at increased risk of adverse neurodevelopmental outcomes would greatly assist in providing appropriate support and interventions earlier, resulting in improved outcomes. However, current methods to detect brain injury around the time of birth lack the sensitivity required to detect the more subtle alterations associated with FGR. Blood biomarkers have this potential. This systematic review assessed the current literature on blood biomarkers for identifying FGR infants at increased risk of adverse neurodevelopmental outcomes at >12 months after birth. Four databases were searched from inception to 22 February 2024. Articles were assessed for meeting the inclusion criteria by two reviewers. The quality of the included article was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. A summary of findings is presented as insufficient articles were identified for meta-analysis. Excluding duplicates, 1,368 records were screened with only 9 articles considered for full text review. Only one article met all the inclusion criteria. Quality assessment indicated low risk of bias. Both blood biomarkers investigated in this study, neuron specific enolase and S100B, demonstrated inverse relationships with neurodevelopmental assessments at 2 years. Four studies did not meet all the inclusion criteria yet identified promising findings for metabolites and cytokines which are discussed here. These findings support the need for further research and highlight the potential for blood biomarkers to predict adverse outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=369242, Identifier CRD42022369242.

TFEB safeguards trophoblast syncytialization in humans and mice.

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.

Prenatal exposure to environmental phenols and fetal growth across pregnancy in the LIFECODES fetal growth study.

INTRODUCTION: Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy. OBJECTIVE: Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth. METHODS: Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth. RESULTS: We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98). DISCUSSION: We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period.

Placental pathology lesions: International Society for Ultrasound In Obstetrics And Gynecology vs. Society for Maternal-Fetal Medicine Fetal growth restriction definitions.

BACKGROUND: Research on the definition of fetal growth restriction has focused on predicting adverse perinatal outcomes. A significant limitation of this approach is that the individual outcomes of interest could be related to the condition and the treatment. Evaluation of outcomes that reflect the pathophysiology of fetal growth restriction may overcome this limitation. OBJECTIVE: To compare the diagnostic performance of the fetal growth restriction definitions established by the International Society for Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome. STUDY DESIGN: In this retrospective cohort study of singleton pregnancies, the International Society for Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine guidelines were used to identify pregnancies with fetal growth restriction and a corresponding control group. The primary outcome was the prediction of placental histopathological findings associated with placental insufficiency, defined as lesions associated with maternal vascular malperfusion. A composite adverse neonatal outcome (i.e., umbilical artery pH≤7.1, Apgar score at 5 minutes ≤4, neonatal intensive care unit admission, hypoglycemia, respiratory distress syndrome requiring mechanical ventilation, intrapartum fetal distress requiring expedited delivery, and perinatal death) was investigated as a secondary outcome. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver-operating-characteristics curves were determined for each fetal growth restriction definition. Logistic regression models were used to assess the association between each definition and the studied outcomes. A subgroup analysis of the diagnostic performance of both definitions stratifying the population in early and late fetal growth restriction was also performed. RESULTS: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (International Society for Ultrasound in Obstetrics and Gynecology adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; Society for Maternal-Fetal Medicine adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (International Society for Ultrasound in Obstetrics and Gynecology adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; Society for Maternal-Fetal Medicine adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both fetal growth restriction definitions had a limited discriminatory capacity for placental histopathological findings of maternal vascular malperfusion and the composite adverse neonatal outcome (area under the receiver-operating-characteristics curve International Society for Ultrasound in Obstetrics and Gynecology 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics Society for Maternal-Fetal Medicine 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62]). CONCLUSIONS: The International Society for Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine fetal growth restriction definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome.

Placental somatic mutation in human stillbirth and live birth: A pilot case-control study of paired placental, fetal, and maternal whole genomes.

INTRODUCTION: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7). DISCUSSION: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.

Cardiac programming in the placentally restricted sheep fetus in early gestation.

Fetal growth restriction (FGR) occurs in 8% of human pregnancies, and the growth restricted newborn is at a greater risk of developing heart disease in later adult life. In sheep, experimental restriction of placental growth (PR) from conception results in FGR, a decrease in cardiomyocyte endowment and an upregulation of pathological hypertrophic signalling in the fetal heart in late gestation. However, there is no change in the expression of markers of cellular proliferation nor in the level of cardiomyocyte apoptosis in the heart of the PR fetus in late gestation. This suggests that FGR arises early in gestation and programs a decrease in cardiomyocyte endowment in early, rather than late, gestation. Here, control and PR fetal sheep were humanely killed at 55 days' gestation (term, 150 days). Fetal body and heart weight were lower in PR compared with control fetuses and there was evidence of sparing of fetal brain growth. While there was no change in the proportion of cardiomyocytes that were proliferating in the early gestation PR heart, there was an increase in measures of apoptosis, and markers of autophagy and pathological hypertrophy in the PR fetal heart. These changes in early gestation highlight that FGR is associated with evidence of early cell death and compensatory hypertrophic responses of cardiomyocytes in the fetal heart. The data suggest that early placental restriction results in a decrease in the pool of proliferative cardiomyocytes in early gestation, which would limit cardiomyocyte endowment in the heart of the PR fetus in late gestation. KEY POINTS: Placental restriction leading to fetal growth restriction (FGR) and chronic fetal hypoxaemia in sheep results in a decrease in cardiomyocyte endowment in late gestation. FGR did not change cardiomyocyte proliferation during early gestation but did result in increased apoptosis and markers of autophagy in the fetal heart, which may result in the decreased endowment of cardiomyocytes observed in late gestation. FGR in early gestation also results in increased hypoxia inducible factor signalling in the fetal heart, which in turn may result in the altered expression of epigenetic regulators, increased expression of insulin-like growth factor 2 and cardiomyocyte hypertrophy during late gestation and after birth.

Choline-An Underappreciated Component of a Mother-to-Be's Diet.

The nutritional status of the mother-to-be has a key impact on the proper development of the fetus. Although all nutrients are important for the developing baby, recent research indicates the importance of adequate choline intake during the periconceptional period, pregnancy, and lactation. Choline plays a key role in the biosynthesis of cell membranes, supporting liver function, neurotransmission, brain development, and DNA and histone methylation. Choline participates in the formation of a child's nervous system, supports its cognitive development, and reduces the risk of neural tube defects. The human body is incapable of producing sufficient choline to meet its needs; therefore, it must be obtained from the diet. Current data indicate that most women in their reproductive years do not achieve the recommended daily intake of choline. The presented narrative review indicates the importance of educating mothers-to-be and thereby increasing their awareness of the effects of choline on maternal and child health, which can lead to a more aware and healthy pregnancy and proper child development.

The value of angiogenetic biomarkers in the detection of early onset fetal growth restriction.

OBJECTIVE: The identification of fetal growth restriction (FGR) due to uteroplacental insufficiency is important to improve perinatal outcomes. To distinguish FGR from small for gestational age (SGA), FGR consensus definition is currently based on biometry and/or additional biophysical parameters. This study aims to verify if this definition might be modified by including circulating angiogenic factors. STUDY DESIGN: This historical cohort study included singleton pregnancies with SGA fetuses after 20 weeks. All patients underwent detailed ultrasound and measurements of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) at first assessment. ISUOG criteria for FGR were applied. Total PlGF was calculated using free PlGF, sFlt-1 and a receptor pharmacology model, and multiple of the median (MoM) values for sFlt-1, free PlGF, total PlGF and sFlt-1/PlGF ratio were calculated to adjust for gestational age. RESULTS: 72 pregnancies with SGA were first evaluated at median (IQR) of 28+5 (26+2 -31+3) weeks' gestation, and 51 fetuses (70.8 %) satisfied the FGR consensus definition. Pregnancies with FGR showed significantly lower levels of free and total PlGF MoM (0.12, 95 % IQR: 0.07-0.36 vs 0.32, 95 % IQR: 0.20-0.53, p = 0.008) and 0.26, 95 % CI: 0.16-0.55 vs 0.43, 95 % IQR: 0.23-0.53, p = 0.028) respectively; and higher sFlt-1 MoM (4.62, 95 % IQR: 1.80-7.30 vs 1.74, 95 % IQR:1.11-3.61, p = 0.014) than pregnancies not classified as FGR. Free and total PlGF MoM correlated significantly with gestational age at delivery (r = 0.776, p < 0.001 and r = 0.707, p < 0.001, respectively). sFlt-1 MoM and sFlt-1/PlGF ratio MoM also correlated with gestational age at delivery (r = -0.681, p < 0.001 and r = -0.823, p < 0.001). Six cases identified as FGR at first ultrasound were not confirmed at birth showing significantly higher levels of free PlGF MoM (0.77, 95 % IQR: 0.27-3.07 vs 0.17, 95 % IQR: 0.08-0.43, p = 0.022). CONCLUSION: These findings show that total as well as free PlGF levels are lower in pregnancies affected with placental growth restriction. Angiogenic biomarkers might improve the differentiation between placental growth restriction and constitutional smallness. Further studies are needed to determine how to integrate them into the current definitions of FGR.

A Comprehensive and Longitudinal View of Pregnancy from the Perspective of the Couple, Maternal Mental Health and Fetal Growth.

OBJECTIVE: This study investigates the impact of both maternal psychopathological factors and adaptive psychological changes within the couple on fetal growth, emphasizing the importance of evaluating pregnancy from the perspectives of the couple, the mother, and the fetus collectively. A "couple" in this context refers to heterosexual partners engaged in the pregnancy process together, whether married or in a stable relationship. METHODS: We included 189 pregnant women in their first trimester, tracking maternal depression, anxiety, body appreciation, prenatal attachment, and the couple's adjustment level across each trimester. Fetal growth parameters measured include biparietal diameter, femur length, humerus length, abdomen circumference, head circumference, ß-HCG, and amniotic fluid levels, with relationships between these variables being modeled accordingly. RESULTS: Our findings indicate stable levels of maternal depression, anxiety, body appreciation, and couple's adjustment throughout the pregnancy, with a significant increase in prenatal attachment levels in each subsequent trimester. Prenatal attachment in the first trimester and maternal depression levels in the second and third trimesters were found to directly influence fetal growth, while other variables exhibited indirect effects. CONCLUSIONS: Fetal growth is influenced by a myriad of biopsychosocial factors. Ensuring healthy pregnancy and fetal development necessitates close monitoring and support of the mother's adaptive psychological changes, early identification and treatment of potential psychopathologies, and maintenance of the psychosocial health of the couple.

Molecular regulators of defective placental and cardiovascular development in fetal growth restriction.

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development.

Maternal rest improves growth in small-for-gestational-age fetuses (<10th percentile).

BACKGROUND: Optimal management of fetuses diagnosed as small for gestational age based on an estimated fetal weight of <10th percentile represents a major clinical problem. The standard approach is to increase fetal surveillance with serial biometry and antepartum testing to assess fetal well-being and timing of delivery. Observational studies have indicated that maternal rest in the left lateral position improves maternal cardiac output and uterine blood flow. However, maternal bed rest has not been recommended based on the results of a randomized clinical trial that showed that maternal rest does not improve fetal growth in small-for-gestational-age fetuses. This study was conducted to revisit this question. OBJECTIVE: This study aimed to determine whether maternal bed rest was associated with an increase in the fetal biometric parameters that reflect growth after the diagnosis of a small-for-gestational-age fetus. STUDY DESIGN: A retrospective study was conducted on fetuses who were diagnosed as small for gestational age because of an estimated fetal weight of <10th percentile for gestational age. The mothers were asked to rest in the left lateral recumbent position. Fetal biometry was performed 2 weeks after the diagnosis. All fetuses before entry into the study had a previous ultrasound that demonstrated an estimated fetal weight of >10th percentile. To assess the response to bed rest, the change in fetal biometric parameters (estimated fetal weight, head circumference, abdominal circumference, and femur length) after the recommendation of bed rest was computed for 2 periods: (1) before the diagnosis of a weight of <10th percentile vs at the time of diagnosis of a weight of <10th percentile and (2) at the time of diagnosis of a weight of <10th percentile vs 2 weeks after maternal bed rest. For repeated measures, proportions were compared using the McNemar test, and percentile values were compared using the Kruskal-Wallis test. A P value of <.05 was considered significant. To describe changes in the estimated fetal weight without bed rest, 2 control groups in which the mothers were not placed on bed rest after the diagnosis of a small-for-gestational-age fetus were included. RESULTS: A total of 265 fetuses were observed before and after maternal bed rest. The following were observed in this study: (1) after 2 weeks of maternal rest, 199 of 265 fetuses (75%) had a fetal weight of >10th percentile; (2) the median fetal weight percentile increased from 6.8 (interquartile range, 4.4-8.4) to 18.0 (interquartile range, 9.5-29.5) after 2 weeks of bed rest; (3) similar trends were noted for the head circumference, abdominal circumference, and femur length. In the groups of patients who were not asked to be on bed rest, a reassignment to a weight of >10th percentile at a follow-up examination only occurred in 7 of 37 patients (19%) in the Texas-Michigan group and 13 of 111 patients (12%) in the Colorado group compared with the bed rest group (199/265 [75%]) (P<.001). CONCLUSION: Patients who were prescribed 2 weeks of bed rest after the diagnosis of a fetal weight of <10th percentile had an increase in weight of >10th percentile in 199 of 265 fetuses (75%). This increase in fetal weight was significantly higher than that in the 2 control groups in which bed rest was not prescribed. This observation suggests that bed rest improves fetal growth in a subset of patients.

Effect of gestational diabetes on fetal growth rate and later overweight in the offspring.

CONTEXT: Children of women with gestational diabetes (GDM) are often born with a higher birthweight and have an increased risk of overweight during childhood. High fetal growth rate is also associated with being overweight in childhood. OBJECTIVE: To examine excessive fetal growth rate as a mediator between GDM and overweight in the offspring. METHODS: This was a longitudinal cohort study, using routinely collected data on children born 2008-2014 in Aarhus, Denmark. Fetal biometrics were extracted from the patient records at Aarhus University Hospital and childhood weight from the health records at Aarhus Municipality Healthcare Service. We calculated growth trajectories for fetuses affected by GDM and for unaffected fetuses using cubic mixed model regression. We extracted individual fetal growth rate and estimated the contributing effect of fetal growth rate on the risk of being overweight in the 5-9 year-old offspring. RESULTS: We included 6794 mother-child pairs, 295 with GDM. Fetal growth was higher in women with GDM from week 25, and the offspring had an increased risk of being overweight (OR: 2.02 (95%CI: 1.44 - 2.84)). When adjusting for fetal growth rate in week 28 the effect attenuated by 15%, and to 1.10 (95%CI: 0.76 - 1.60) when further adjusting for pre-pregnancy BMI. CONCLUSION: Pregnancies affected by GDM had higher fetal growth rate and the offspring had a higher risk of being overweight at 5-9 years. Fetal growth rate in early third trimester was a mediator of up to 15% of this association, but pre-pregnancy BMI contributed strongly as well.