Relative uteroplacental insufficiency of labor.

Relative uteroplacental insufficiency of labor (RUPI-L) is a clinical condition that refers to alterations in the fetal oxygen "demand-supply" equation caused by the onset of regular uterine activity. The term RUPI-L indicates a condition of "relative" uteroplacental insufficiency which is relative to a specific stressful circumstance, such as the onset of regular uterine activity. RUPI-L may be more prevalent in fetuses in which the ratio between the fetal oxygen supply and demand is already slightly reduced, such as in cases of subclinical placental insufficiency, post-term pregnancies, gestational diabetes, and other similar conditions. Prior to the onset of regular uterine activity, fetuses with a RUPI-L may present with normal features on the cardiotocography. However, with the onset of uterine contractions, these fetuses start to manifest abnormal fetal heart rate patterns which reflect the attempt to maintain adequate perfusion to essential central organs during episodes of transient reduction in oxygenation. If labor is allowed to continue without an appropriate intervention, progressively more frequent, and stronger uterine contractions may result in a rapid deterioration of the fetal oxygenation leading to hypoxia and acidosis. In this Commentary, we introduce the term relative uteroplacental insufficiency of labor and highlight the pathophysiology, as well as the common features observed in the fetal heart rate tracing and clinical implications.

Mid-pregnancy circulating cytokine levels, placental efficiency and their relationship with preterm birth.

Objective: To assess a panel of cytokines and placental insufficiency with the risk of preterm delivery (PTD). Methods: Nested case-control study into the BRISA birth cohort. Eighty-two mother-infant-placenta pairs were selected at 20+0 to 25+6 weeks. Circulating biomarker levels were performed using Luminex flowmetric xMAP technology. Cytokines classified as Th1, Th2 or Th17 and other biomarkers were selected. The ratio between birth weight and placental weight (BW/PW) was used as a proxy for placental efficiency. Spearman correlation, univariate analyses and logistic regression models were calculated. Sensitivity, specificity, positive and negative likelihood ratios were calculated using the Receiver Operating Characteristic curve. Results: Mean gestational age was 250 days, 14,6% were small for gestational age, 4,8% large for gestational age and 13,4% stunted. Placental efficiency was higher for term newborns (p<0,001), and 18/22 (81%) preterm biomarker values were higher than the control group. Th1 cytokines were highly correlated, while the weakest correlation was observed in other biomarkers. Less education was associated with a higher risk of PTD (p = 0.046), while there was no appreciable difference in the risk of PTD for placental insufficiency. Biomarkers showed negligible adjusted OR of PTD (0.90 to 1.02). IL-6, IL-8, IL-1ß, TNFß, IL-4, IL-13, GCSF, MIP1A, VEGF, EGF, and FGF2 presented a higher sensitivity ranging from 75.56% to 91.11%. Conclusion: IL-8, IL-12p40, IL-4, IL-13, GCSF, MIP1B, and GMSF in asymptomatic pregnant women were associated with PTD. This finding suggests an activation of maternal inflammatory response.

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.

MRI assessed placental volume and adverse pregnancy outcomes: Secondary analysis of prospective cohort study.

INTRODUCTION: Our goal was to evaluate the potential utility of magnetic resonance imaging (MRI) placental volume as an assessment of placental insufficiency. METHODS: Secondary analysis of a prospective cohort undergoing serial placental MRIs at two academic tertiary care centers. The population included 316 participants undergoing MRI up to three times throughout gestation. MRI was used to calculate placental volume in milliliters (ml). Placental-mediated adverse pregnancy outcome (cAPO) included preeclampsia with severe features, abnormal antenatal surveillance, and perinatal mortality. Serial measurements were grouped as time point 1 (TP1) <22 weeks, TP2 22 0/7-29 6/7 weeks, and TP3 ≥30 weeks. Mixed effects models compared change in placental volume across gestation between cAPO groups. Association between cAPO and placental volume was determined using logistic regression at each TP with discrimination evaluated using area under receiver operator curve (AUC). Placental volume was then added to known clinical predictive variables and evaluated with test characteristics and calibration. RESULTS: 59 (18.7 %) of 316 participants developed cAPO. Placental volume growth across gestation was slower in the cAPO group (p < 0.001). Placental volume was lower in the cAPO group at all time points, and alone was moderately predictive of cAPO at TP3 (AUC 0.756). Adding placental volume to clinical variables had moderate discrimination at all time points, with strongest test characteristics at TP3 (AUC 0.792) with sensitivity of 77.5 % and specificity of 75.3 % at a predicted probability cutoff of 15 %. DISCUSSION: MRI placental volume warrants further study for assessment of placental insufficiency, particularly later in gestation.

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 (FGR) 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 FGR may overcome this limitation. OBJECTIVE: To compare the diagnostic performance of the FGR definitions established by the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal-Fetal Medicine (SMFM) to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome (ANeO). STUDY DESIGN: In this retrospective cohort study of singleton pregnancies, the ISUOG and the SMFM guidelines were used to identify pregnancies with FGR 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 (MVM). A composite ANeO (ie, 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 FGR 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 FGR was also performed. RESULTS: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (ISUOG adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; SMFM adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (ISUOG adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; SMFM adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both FGR definitions had a limited discriminatory capacity for placental histopathological findings of MVM and the composite ANeO (area under the receiver-operating-characteristics curve ISUOG 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics SMFM 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62]). CONCLUSION: The ISUOG and the SMFM FGR definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite ANeO. El resumen está disponible en Español al final del artículo.

Pregnancy outcomes in correlation with placental histopathology in pregnancies complicated by fetal growth restriction with vs. without reduced fetal movements.

PURPOSE: Fetal movements are crucial indicators of fetal well-being, with reduced fetal movements (RFM) suggesting potential fetal compromise. Fetal growth restriction (FGR), often linked to placental insufficiency, is a major cause of perinatal morbidity and mortality. This study aimed to investigate the neonatal, labor, and placental outcomes of FGR pregnancies with and without RFM at term. METHODS: In this retrospective study, data from all term, singleton deliveries with FGR and concomitant RFM were obtained and compared to an equal control group of FGR without RFM. Maternal characteristics, pregnancy and neonatal outcomes, and placental histology were compared. The primary outcome was a composite of adverse neonatal outcomes. A multivariable regression analysis was performed to identify independent associations with adverse neonatal outcomes. RESULTS: During the study period, 250 FGR neonates with concomitant RFM and an equal control group were identified. The groups did not differ in maternal demographics aside from significantly higher rates of maternal smoking in the RFM group (p < 0.001). Polyhydramnios and oligohydramnios (p = 0.032 and p = 0.007, respectively) and meconium-stained amniotic fluid (p < 0.001) were more prevalent in the FGR+RFM group. Additionally, the RFM group showed higher rates of adverse neonatal outcomes despite having larger neonates (p = 0.047 and p < 0.001, respectively). No significant differences were observed in placental findings. Logistic regression identified RFM as an independent predictor of adverse neonatal outcomes (aOR 2.45, 95% CI 1.27-4.73, p = 0.008). CONCLUSION: Reduced fetal movements are significant and independent predictors of worse neonatal outcomes in FGR pregnancies, suggesting an additional acute insult on top of underlying placental insufficiency.

Maternal serum biomarkers of placental insufficiency at 24-28 weeks of pregnancy in relation to the risk of delivering small-for-gestational-age infant in Sylhet, Bangladesh: a prospective cohort study.

BACKGROUND: Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA. METHODS: Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders. RESULTS: The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025). CONCLUSIONS: This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.

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.

Paternal microbiome perturbations impact offspring fitness.

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

Assessment of feto-placental oxygenation and perfusion in a rat model of placental insufficiency using T2* mapping and 3D dynamic contrast-enhanced MRI.

INTRODUCTION: Placental insufficiency may lead to preeclampsia and fetal growth restriction. There is no cure for placental insufficiency, emphasizing the need for monitoring fetal and placenta health. Current monitoring methods are limited, underscoring the necessity for imaging techniques to evaluate fetal-placental perfusion and oxygenation. This study aims to use MRI to evaluate placental oxygenation and perfusion in the reduced uterine perfusion pressure (RUPP) model of placental insufficiency. METHODS: Pregnant rats were randomized to RUPP (n = 11) or sham surgery (n = 8) on gestational day 14. On gestational day 19, rats imaged using a 7T MRI scanner to assess oxygenation and perfusion using T2* mapping and 3D-DCE MRI sequences, respectively. The effect of the RUPP on the feto-placental units were analyzed from the MRI images. RESULTS: RUPP surgery led to reduced oxygenation in the labyrinth (24.7 ± 1.8 ms vs. 28.0 ± 2.1 ms, P = 0.002) and junctional zone (7.0 ± 0.9 ms vs. 8.1 ± 1.1 ms, P = 0.04) of the placenta, as indicated by decreased T2* values. However, here were no significant differences in fetal organ oxygenation or placental perfusion between RUPP and sham animals. DISCUSSION: The reduced placental oxygenation without a corresponding decrease in perfusion suggests an adaptive response to placental ischemia. While acute reduction in placental perfusion may cause placental hypoxia, persistence of this condition could indicate chronic placental insufficiency after ischemic reperfusion injury. Thus, placental oxygenation may be a more reliable biomarker for assessing fetal condition than perfusion in hypertensive disorders of pregnancies including preeclampsia and FGR.

The associations between maternal and fetal exposure to endocrine-disrupting chemicals and asymmetric fetal growth restriction: a prospective cohort study.

Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary's Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (ß = 0.003, p < 0.05). When comparing the normal growth and asymmetric FGR groups, the asymmetric FGR group showed significantly higher maternal and fetal BPA levels compared to the normal growth group (maternal urine BPA, 3.99 µg/g creatinine vs. 1.71 µg/g creatinine [p < 0.05]; cord blood BPA, 1.96 µg/L vs. -0.86 µg/L [p < 0.05]). In conclusion, fetal exposure levels of BPA show linear associations with asymmetric fetal growth patterns. High maternal and fetal exposure to BPA might be associated with asymmetric FGR.

Placentae of small appropriately-grown-for-gestational-age neonates exhibit sexually dimorphic transcriptomic changes representative of placental insufficiency.

INTRODUCTION: Previous studies have reported that neonates less than the 25th BWC especially if they were male, were more likely to be associated with birth complications suggesting small neonates often identified as appropriately grown are at risk of adverse outcomes. We have questioned whether smaller neonates not typically categorized as "small for gestational age" may not reach their genetically determined growth due to placental insufficiency. METHODS: RNA-Seq was performed on the Illumina NovaSeq 600 using term placentae from neonates that were less than the 10th birthweight centile (BWC) (n = 39), between the 10th and the 30th BWC (n = 15) or greater than the 30th BWC (n = 23). Bioinformatic analyses were conducted and statistical significance was assessed at a level of P < 0.05 for single comparisons or FDR <0.05 unless otherwise noted. RESULTS: Gene set enrichment analysis revealed differences between BWC groups and in relation to the sex of the placenta. Genes associated with hypoxia, inflammatory responses, estrogen responsive genes, and androgen responsive genes were enriched (FDR <0.1) for in placentae of neonates <10th BWC regardless of sex and also in male placentae of neonates between the 10th-30th BWC. Female placenta of neonates between the 10th-30th BWC were comparable to placentae of neonates >30th BWC. DISCUSSION: These findings provide evidence that small male neonates may be at a greater risk of an adverse outcome than females due to changes in gene expression that are associated with placental dysfunction. The current data raises questions of whether placental pathology for smaller appropriately grown neonates should be scientifically and clinically examined in more depth.

A longitudinal and cross-sectional study of placental circulation between normal and placental insufficiency pregnancies.

INTRODUCTION: To longitudinally and cross-sectionally study the differences in the uterine artery pulsatility index (UTPI), umbilical artery pulsatility index (UAPI) and placental vascularization indices (PVIs, derived from 3-dimensional power Doppler) between normal and placental insufficiency pregnancies throughout gestation. METHODS: UTPI, UAPI and PVI were measured 6 times at 4- to 5- week intervals from 11 to 13+6 weeks-36 weeks. Preeclampsia (PE) and fetal growth restriction (FGR) were defined as placental insufficiency. Comparisons of UTPI, UAPI and PVI between normal and insufficiency groups were performed by one-way repeated measures analysis of variance. RESULTS: A total of 125 women were included: monitored regularly from the first trimester to 36 weeks of gestation: 109 with normal pregnancies and 16 with placental insufficiency. Longitudinal study of the normal pregnancy group showed that UTPI and UAPI decreased significantly every 4 weeks, while PVIs increased significantly every 8 weeks until term. In the placental insufficiency group however, this decrease occurred slower at 8 weeks intervals and UTPI stabilized after 24 weeks. No significant difference was noted in PVIs throughout pregnancy. Cross-sectional study from different stages of gestation showed that UTPI was higher in the insufficiency group from 15 weeks onward and PVIs were lower after 32 weeks. DISCUSSION: Compared to high-risk pregnancies with normal outcome, UTPI and UAPI needed a longer time to reach a significant change in those with clinical confirmation of placental insufficiency pregnancies and no significant change was found in PVI throughout gestation. UTPI was the earliest factor in detecting adverse outcome pregnancies.

Phenotype of early-onset fetal growth restriction in sheep.

Introduction: Fetal growth restriction (FGR) is a common pregnancy complication, caused by placental insufficiency, with serious adverse consequences for development in utero and postnatal wellbeing. There are no antenatal treatments to improve growth or organ development in FGR, and animal models are essential to mimic the physiological adaptations in FGR and to assess potential interventions. This study aimed to identify the temporal nature of reduced developmental trajectory in fetuses with FGR, and to examine the effects of common factors that may mediate differential growth such as glucocorticoid treatment. We hypothesised that the trajectory of growth would be adversely impacted by FGR. Methods: FGR was induced via surgical placental insufficiency in fetal sheep (89 days gestation/0.6 gestation; n=135) and compared to age-matched controls over the last third of gestation and into neonatal life (n=153). Results: Body weight of FGR fetuses/lambs was significantly reduced compared to controls (p<0.0001) from 127 days of gestation (term is 148 days), with increased brain:body weight ratio (p<0.0001) indicative of brain sparing. All biometric measures of body size were reduced in the FGR group with the exception of biparietal (head) diameter. The trajectory of body growth in the last trimester of sheep pregnancy was significantly reduced in the FGR group compared to controls, and stillbirth rate increased with longer gestation. Discussion: This work provides a well characterised FGR animal model that mimics the known physiological adaptations in human pregnancy and can be used to determine the efficacy of potential interventions.

The role of placental insufficiency in spontaneous preterm birth: A literature review.

Preterm Birth (delivery before 37 weeks of gestation) is the leading cause of childhood mortality and is also associated with significant morbidity both in the neonatal period and beyond. The aetiology of spontaneous preterm birth is unclear and likely multifactorial incorporating factors such as infection/inflammation and cervical injury. Placental insufficiency is emerging as an additional contributor to spontaneous preterm delivery; however, the mechanisms by which this occurs are not fully understood. Serum biomarkers and imaging techniques have been investigated as potential predictors of placental insufficiency, however none have yet been found to have a sufficient predictive value. This review examines the evidence for the role of the placenta in preterm birth, preterm prelabour rupture of the membranes and abruption as well as highlighting areas where further research is required.

Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.

We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband's genotype-phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband's mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain.

Pregnancy in antiphospholipid syndrome: what should a rheumatologist know?

This review focuses on the management of reproductive issues in women who have antiphospholipid syndrome (APS) or are carriers of antiphospholipid antibodies (aPL). The importance of aPL detection during preconception counselling relies on their pathogenic potential for placental insufficiency and related obstetric complications. The risk of adverse pregnancy outcomes can be minimized by individualized risk stratification and tailored treatment aimed at preventing placental insufficiency. Combination therapy of low-dose acetylsalicylic acid and heparin is the mainstay of prophylaxis during pregnancy; immunomodulation, especially with hydroxychloroquine, should be considered in refractory cases. Supplementary ultrasound surveillance is useful to detect fetal growth restriction and correctly tailor the time of delivery. The individual aPL profile must be considered in the stratification of thrombotic risk, such as during assisted reproduction techniques requiring hormonal ovarian stimulation or during the follow-up after pregnancy in order to prevent the first vascular event.

Leptin deficiency, a potential mechanism for impaired fetal lung development in uteroplacental insufficiency?

Uteroplacental insufficiency (UPI) is a major cause of fetal growth restriction (FGR). Leptin, an adipokine, has been shown to play a vital role in fetal organogenesis. There is evidence reporting leptin deficiency in preterm and growth-restricted fetuses. In this issue of Pediatric Research, Yuliana et al. report leptin expression and lung development in UPI-induced FGR rats. UPI-induced FGR rats expressed decreased lung leptin and had impaired lung development, as shown by decreased surface area and lung volume. They also found a significant association between lung radial alveolar count, serum leptin, von Willebrand factor, and specific metabolites on metabolomic analyses. Previous studies on leptin supplementation in vivo have been associated with improvement in lung maturation; supporting the evidence, that leptin improves lung growth and development in FGR and may have future therapeutic potential in the improvement of respiratory outcomes in these infants. Future studies to support evidence of this association in humans are warranted.

Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction.

BACKGROUND: Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR. METHODS: Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected. RESULTS: Study groups were control (n = 5), FGR (n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined (p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule (p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex. CONCLUSIONS: Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation. IMPACT: Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination. This preclinical study adds to the body of work on this topic, and informs clinical translation. Neuroprotection likely to improve long-term outcomes of this vulnerable infant group.