Asymmetric Fetal Growth Restriction Research Articles

Sex Differences in Impacts of Early Gestational and Peri-Adolescent Ozone Exposure on Lung Development in Rats: Implications for Later Life Disease in Humans

Air pollution exposure during pregnancy may affect fetal growth. Fetal growth restriction (FGR) is associated with reduced lung function in children that can persist into adulthood. Using an established model of asymmetrical FGR in Long-Evans rats, this study investigated sex differences in effects of early life ozone exposure on lung development and maturation. Adverse health effects for i) gestational exposure (with impacts on primary alveolarization), ii) peri-adolescent exposure (with impacts on secondary alveolarization), and iii) cumulative exposure across both periods were evaluated. Notably, female offspring were most affected by gestational ozone exposure, likely because of impaired angiogenesis and corresponding decreases in primary alveolarization. Females had diminished lung capacity, fewer mature alveoli, and medial hypertrophy of small and large pulmonary arteries. Males, especially FGR-prone offspring, were more affected by peri-adolescent ozone exposure. Males had increased ductal areas, likely due to disrupted secondary alveolarization. Altered lung development may increase risk of developing diseases, such as pulmonary arterial hypertension or chronic obstructive pulmonary disease. Pulmonary arterial hypertension disproportionately affects women. In the United States, chronic obstructive pulmonary disease prevalence is increasing, especially in women; and prevalence for both men and women is highest in urbanized areas. This investigation underlines the importance of evaluating results separately by sex, and provides biologic plausibility for later consequences of early-life exposure to ozone, a ubiquitous urban air pollutant.

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 (β = 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.

Subclinical myocardial dysfunction among fetal growth restriction neonates: a case-control study

Objectives To evaluate cardiac structural and functional changes in neonates with fetal growth restriction (FGR) compared to appropriate-for-gestational-age (AGA) neonates using conventional echocardiography, tissue Doppler imaging (TDI), and speckle tracking echocardiography. Method This case-control study included 85 FGR neonates and 75 non-FGR, weight adequate for gestational age neonates. Among these, 37 were symmetric FGR and 48 were asymmetric FGR. All the biophysical profiles of these newborns were assessed. An echocardiographic test was performed to evaluate cardiac dimension, Left ventricular ejection fraction (LV EF), Mitral valve Doppler flow velocities, myocardial performance index, tissue annular velocities, and LV global longitudinal strain (GLS). Results Although LVEF was found to be within the normal range, mean EF was reduced among neonates with FGR than non-FGR controls (EF: 66.14 ± 3.85% vs 69.46 ± 3.58%; p < 0.001, in FGR and non-FGR, respectively). Furthermore, LV E/E’ a measure of LV diastolic function was altered among both types of FGR neonates. Similarly, LV GLS was reduced among FGR neonates (LV GLS: −20.69 ± 2.7% vs −19.06 ± 2.9%; p < 0.001 in non-FGR and FGR, respectively). Conclusion FGR neonates exhibit significant alterations in cardiac geometry compared to AGA controls. FGR neonates also demonstrated a significant reduction in LV EF, FS, and LV global longitudinal strain, depicting failure to adapt to the increased cardiac workload after birth.

Abstract 11586: Therapeutic Potential of Alpha Lipoic Acid in a Rat Model of Superimposed Preeclampsia: Effect on Maternal Signs, Placental Development and Fetal Growth

Introduction: Superimposed preeclampsia (SPE) occurs in 25-40% of pregnant women affected by chronic hypertension and is associated with adverse maternal and neonatal outcomes. In previous studies, we have demonstrated that pregnant Stroke-prone Spontaneously Hypertensive Rat represent a spontaneous SPE model, characterized by defective trophoblast invasion and placental oxidative stress, asymmetric fetal growth restriction and worsening maternal hypertension with renal dysfunction towards term. Here, we sought to evaluate the therapeutic potential of alpha lipoic acid (ALA), a potent antioxidant, during early pregnancy in this model. Methods: Congenic timed breedings were established using SHRSP and Wistar Kyoto (WKY) females (10-12 weeks old, 200-250 g body weight, N = 10 animals/day analyzed). Upon vaginal plug detection (gestation day (GD)1), dams were assigned to two groups: ALA treatment, injected 25mg/kg body weight ALA i.p. on GD1, GD8 and GD12 and controls, receiving saline following the same protocol. Systolic blood pressure (SBP) profiles throughout pregnancy were recorded using a noninvasive volume pressure recording device. On GD20, animals were euthanized and fetoplacental specimens isolated for morphological and molecular analyzes. Statistical analysis was run on GraphPad Prism v 8.0, using 2 way ANOVA. Statistical significance was set at p˂ 0.05. Results: Treatment with ALA prevented the pregnancy-dependent SBP increase typical of the SHRSP model (SBP GD14 SHRSP: 169.3±2.1 mmHg vs. SHRSP+ALA: 146.1±3.4, p˂0.001). Furthermore, fetuses carried by ALA-treated SHRSP displayed increased weights (SHRSP: 1.75±0.05g vs. SHRSP+ALA: 1.99±0.01g, p˂0.05) and decreased cephalization indexes on GD20, indicating an improvement in the asymmetric growth restriction pattern. Treated dams also presented increased numbers of glycogen trophoblasts (PAS + cells) in the junctional zone and an enhanced vessel density on Isolectin B4 + staining, suggesting an improved placental function. Conclusions: ALA administration during early pregnancy in the SHRSP model ameliorated maternal signs and improved placental function and fetal growth, emerging as a novel therapeutic intervention in pregnancies affected by chronic hypertension

Placental T-Cadherin Correlates With Trophoblastic Invasion Anomalies: Placenta Percreta and Fetal Growth Restriction.

In this study, we compared the placental T-cadherin staining intensity of pregnant women with placenta percreta (PP) and asymmetrical fetal growth restriction (FGR) compared with healthy control pregnancies. Placental T-cadherin levels of the placenta of 86 pregnant women in total, 25 with FGR, 30 with healthy pregnant subjects, and 31 with PP, were examined using monoclonal anti-T-cadherin (CDH13) antibody for immunohistochemical examination. In immunohistochemistry, H -scores were used for each group to compare the expression of T-cadherin in extravillous trophoblast (EVT) cells. T-cadherin H -score of EVTs was highest in the FGR group and the lowest in the PP group. The difference in H -score between the FGR group and the control group was not statistically significant ( P =0.344). The difference between the PP group and the other 2 groups was significant ( P <0.0001). Multivariable linear regression analysis with a stepwise elimination method was performed in order to identify demographic and clinical parameters with significant effects on the T-cadherin H -score of EVTs. The estimation results identified only the disease group as a significant predictor of the H -score of EVTs ( R2 =0.340, P <0.0001). The highest T-cadherin H -score of EVTs was found in the FGR group and the lowest in the PP group. The low T-cadherin H-score values in the PP group suggest that low T-cadherin EVTs may be associated with increased placental invasion. Likewise, despite the statistical insignificance, a higher T-cadherin H -score of EVTs in FGR compared with controls implies a decreased invasiveness of the placenta in FGR.

The Genetic and Clinical Outcomes in Fetuses With Isolated Fetal Growth Restriction: A Chinese Single-Center Retrospective Study.

Objective: To evaluate the utility of a chromosomal microarray (CMA) in fetuses with isolated fetal growth restriction (FGR) and explore risk factors for the prediction of chromosomal aberration and perinatal adverse outcomes. Method: This study included 271 fetuses of estimated fetal weight less than the 3rd percentile without other structural malformation. Early-onset and late-onset FGR were defined as gestational weeks less than 32 weeks and more than 32 weeks respectively. These patients underwent quantitative fluorescent polymerase chain reaction (QF-PCR) and CMA as the first-line genetic detection strategy. Chromosomal anomalies were compared after stratified analysis by the early-onset and the late-onset FGR, including the absence or presence of ultrasound soft markers, abnormal amniotic fluid, abnormal umbilical Doppler, and gestational disorders. The follow-up time was within 1 year after birth. Logistic regression was used to seek risk predictors of chromosomal aberration and perinatal adverse outcomes for isolated FGR. Results: The CMA identified clinically significant variants in 18/271 (6.6%) fetuses, and variants of unknown significance (VOUS) in 15/271 (5.5%) fetuses. Stratified analysis showed that there was a higher incidence of clinically significant variants in fetuses with the early-onset FGR compared with late-onset FGR (8.7%, 17/195 vs. 1.3%, 1/76, p < 0.05). Regression analysis showed that early gestational age (GA) at diagnosis of FGR was the major risk factor for chromosomal aberration (OR = 0.846). By variable regression analysis, early GA at diagnosis and decreased estimated fetal weight (EFW) percentile of suspicion of FGR, asymmetrical FGR, abnormal amniotic fluid, and severe preeclampsia could all increase the risk of adverse outcomes of isolated FGR including intra-uterine fetal death (IUFD), termination of pregnancy (TOP), and preterm birth in pregnancies with FGR. Conclusion: This study emphasized the value of microarrays for unbalanced genomic variants in fetuses with isolated FGR, especially since the gestational age of nullipara was less than 32 weeks. Perinatal adverse outcomes of isolated FGR were influenced by multiple factors including GA and estimated fetal weight (EFW) percentile of suspicion of FGR, asymmetrical FGR, abnormal amniotic fluid, and severe preeclampsia.

Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2 ) pregnancy±melatonin (M) treatment (5μg·ml-1 .day-1 ) in the maternal drinking water. Hypoxia±melatonin treatment was from day 15-20 of gestation (term is ca. 22days). To control for possible effects of maternal hypoxia-induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair-fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in-vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair-fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch-up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia-induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair-fed pregnancies. Whilst maternal treatment of normoxic or pair-fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.

77 Role of Placental PAPP-A and IGF-II in placental growth in hypoxia-induced fetal growth restriction

Fetal growth restriction (FGR) is associated with an increased risk of perinatal and neonatal mortality. Insulin-like growth factors (IGFs) play a major role in fetal growth through PAPP-A-IGF signaling. IGF-II, specifically, is involved in development of placental exchange into late gestation. Chronic hypoxia can result in FGR through mechanisms of placental dysfunction. We hypothesize that chronic hypoxia-exposure decreases placental PAPPA- and IGF-II protein expression resulting in FGR. Female guinea pigs (GPs) were time-mated with male GPs. Pregnant sows (term gestation = 65 days) were randomly assigned to either normoxia (NMX, room air, 21% O2) or hypoxia (HPX, 10.5% O2) during the last 14 days of pregnancy. At near-term gestation, anesthetized female fetuses were removed via hysterotomy. Fetal body, organ (brain, liver, heart) and placenta weights (wt) were recorded. Asymmetric FGR was classified as fetal wt 0.66. Placental tissues of 7 NMX and 7 HPX-FGR male GPs were homogenized and protein expression of PAPP-A and IGF-II was measured by Western blot. NMX and HPX were compared using Student’s t-Tests with statistical significance determined at p value < 0.05. In the NMX and HPX-FGR cohorts, there was no statistical difference in the mean gestational age at delivery 63.7d and 62.4d (p=0.07), respectively. As expected, fetal body wt, brain, and liver wt were significantly less in the HPX-FGR cohort as compared to NMX (Table 1). Relative placenta wt was increased by 25% with HPX (p<0.05). There was no statistical difference in PAPP-A expression in NMX and HPX placentas (1.22 ± .28 vs 1.55± .79, p=0.353, respectively). IGF-II expression was significantly increased in HPX-FGR placentas (0.58 ± .13 vs 1.22 ±.34, p=0.05), (Figure 1). Contrary to our hypothesis, neither PAPP-A nor IGF-II were decreased with hypoxia. Rather, hypoxia increased IGF-II, which is consistent with an increase in relative placental wt. This suggests a unique role for IGF-II as mechanism of compensatory placental growth response, despite the presence of FGR.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Maternal high-fructose consumption provokes placental oxidative stress resulting in asymmetrical fetal growth restriction in rats.

We aimed to determine the impact of high-fructose intake during pregnancy on the fetal-placental unit in rats, which may be the initial mechanism of the programming effect of fructose. Pregnant Sprague–Dawley rats were randomly assigned to three groups and respectively provided tap water (n = 10), 10% (w/v) fructose solution (n = 10), and 10% (w/v) glucose solution (n = 10) from embryonic day 0 to 20. Compared with the control and glucose groups, significantly lower fetal length, fetal weight, placental weight, and fetus/placenta ratio were found in the fructose group on embryonic day 20 (all p<0.05). In parallel with markedly increased uric acid concentrations in the dams, significantly decreased antioxidant enzymes activities and mRNA expression levels were observed in placentas in the fructose group (all p<0.05). In the fructose group, placental mRNA and protein expression of nuclear factor erythroid 2-related factor 2 was markedly downregulated and kelch-like ECH-associated protein 1 was significantly upregulated (all p<0.05). In conclusion, high-fructose consumption during pregnancy drives augmented oxidative stress in rats. Placental insufficiency under oxidative stress contributes to asymmetrical fetal growth restriction.

Unusual Presentations of Trisomy 21

AbstractTrisomy 21 is the most common aneuploidy in liveborn infants. Most of the soft markers for trisomy 21 are non-specific and transient. We present 2 cases which had abnormalities which are very rarely associated with Down’s syndrome. In the first case, the patient had bilateral congenital cataract along with an absent nasal bone. In the second case, the patient had severe asymmetric fetal growth restriction at 20 weeks with other multi-system abnormalities. With detailed ultrasound scanning and thorough investigation, we could diagnose trisomy 21 even with such unusual presentations.

Polymorphic variants of bovine ADCY5 gene identified in GWAS analysis were significantly associated with ovarian morphological related traits

The reproductive performance (e.g. fertility) of dairy cows, which declined over past few decades due to the intense and intensive selection, needs to be improved. Previous genome-wide association study (GWAS) of female Holstein screened the Adenylate cyclase 5 (ADCY5) as the candidate gene for cow fertility. As a member of the adenylyl cyclases family, adenylate cyclase 5 (ADCY5) is famous for regulating extrapyramidal motor system related various neuropsychiatric diseases, and its genetic variant is reported to associate with lower birth and placenta weight which leads to asymmetric fetal growth restriction. It was hypothesized that ADCY5 may affect the fertility of cows by regulating the processes of ovarian development. Herein, genomic DNA from 768 ovaries samples of healthy unrelated Holstein cow were used to screen potential insertion/deletion (indel) mutations using eight pairs of primers, and we found three novel polymorphic indel variants, namely, rs385624978 (P3-D11-bp), rs433028962 (P5-I19-bp) and rs382393457 (P8-D19-bp). The minor allelic frequencies (MAF) of P3-D11-bp, P5-I19-bp and P8-D19-bp loci were 0.188, 0.365 and 0.06, respectively, and there were 7 different haplotypes. Additionally, linkage disequilibrium analysis demonstrated no linkage among them. Importantly, P3-D11-bp locus was significantly related to both ovarian width (P = 1.0E-6) and corpus luteum diameter (P = 0.015); P5-I19-bp locus had a significant relation with corpus albicans diameter (P = 0.030) and ovaries with mutational homozygous genotype produced a superior corpus albicans diameter than those with other genotypes. Briefly, three novel indel mutations of bovine ADCY5 gene were identified and two of them were uncovered to be significantly correlated with ovarian phenotypic traits or corpus luteum or albicans traits. These findings contributed to the application of molecular marker-assisted selection (MAS) in improving female fertility in cattle, which could accelerate the development of the cattle industry.

Characteristics of pregnancy and delivery in women with vitamin D deficiency

Vitamin D deficiency is recognized as a public health problem in many countries around the world, with special attention being paid to pregnant women. In the last decade, studies have been conducted to link vitamin D deficiency during pregnancy with a wide range of obstetric and perinatal complications, namely preeclampsia, gestational diabetes, bacterial vaginosis, fetal growth retardation syndrome, low birth weight, impaired fetal formation and bone loss.Purpose. To study the characteristics of pregnancy and childbirth in women with vitamin D deficiency.Materials and methods. The article presents the study results of the pregnancy and childbirth characteristics in women with vitamin D deficiency. In total, 100 pregnant women of reproductive age were examined and two groups were formed: the main group – 50 pregnant women with vitamin D deficiency and the control group – 50 somatically healthy pregnant women with a normal level of 25(OH)D. Three peripheral blood sampling were performed to determine the serum level of 25(OH)D: at 10–12, 20–22 and 30–32 weeks of gestation.Results. As a result of our study, the most common complications of vitamin D deficiency were: risk of pregnancy termination, which was observed in 28 (56.0 %) women of the main group and in 6 (12.0 %) women of the control group, P < 0, 05. The threat of preterm birth was observed in 19 (38.0 %) women of the main group and 7 (14.0 %) women of the control group, P < 0.05. Mild preeclampsia was diagnosed in 18 (36.0 %) women of the main group and in 4 (8.0 %) women of the control group, P < 0.05; moderate preeclampsia was diagnosed in 9 (18.0 %) women of the main group and in none of the control women; severe preeclampsia – in 2 (4.0 %) women of the main group, which was not characteristic of the control group. Based on the glucose tolerance test in women of the main group, the diagnosis of gestational diabetes (GD) was established in 16 (32.0 %) pregnant women in the second trimester and in 7 (14.0 %) in the third trimester. In this study, it was found that GD was accompanied by first degree obesity in 7 (14.0 %) women of the main group. Bacterial vaginosis at 10–12 weeks was diagnosed in 18 pregnant women: in 15 (30.0 %) women of the main group and in 3 (6.0 %) of the control group, – P < 0.05; at 20–22 weeks in – 28 pregnant women: in 21 (42.0 %) women of the main group and in 7 (14.0 %) of the control group, P < 0.05; at 30–32 weeks it was diagnosed in 37 pregnant women: in 26 (52.0 %) women of the main group and in 11 (22.0 %) of the control group, – P < 0.05. Asymmetric fetal intrauterine growth restriction of the 1st degree was found in 6 (12.0 %), the 2nd degree – in 4 (8.0 %) pregnant women of the main group and no case in the control group women was reported.Conclusions. The established multiple actions of vitamin D and a number of obstetrical and perinatal complications, namely gestational diabetes, early and late spontaneous abortions, preterm birth, bacterial vaginosis associated with vitamin D deficiency, underline the urgency of this problem. The findings indicate that screening of pregnant women for serum vitamin D content with the following timely supplementation during pregnancy will help to reduce the incidence of obstetrical and perinatal complications.

Early prenatal detection of triploidy: a 9-year experience in mainland China

Objective In this study, we report the indications for prenatal cytogenetic diagnosis of triploid cases, in an attempt to identify clues to early diagnosis. Study design This was a retrospective analysis of prenatal cases of triploidy during a 9-year period at mainland China. Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, fetal ultrasound findings, and pregnancy outcomes. Results A total of 22 singleton pregnancies affected with triploid fetuses were detected. The fetal karyotype included 69,XXX (72.7%) and 69,XXY (27.3%). Eighteen cases were identified by the first trimester screening program. One case was missed by maternal cell-free DNA testing, but detected by second trimester anatomy scan. Three cases escaped the first trimester screening and were detected by second trimester anatomy scan. Conclusions The present study demonstrates that most triploid cases can be diagnosed prenatally during the first trimester. The early asymmetrical fetal growth restriction, structural anomalies, and extremely high risk serum screening result for trisomy 21 or 18 should alert the physicians to the investigation of triploidy. Key Message Ultrasound-based first-trimester screening plays a major role in early diagnosis of fetal triploidy. Future replacement of routine first-trimester screening by cell-DNA testing might miss the chance of early diagnosis and management of triploid pregnancies.

Chronic hypoxia alters maternal uterine and fetal hemodynamics in the full-term pregnant guinea pig.

Placental hypoxia is associated with maternal hypertension, placental insufficiency, and fetal growth restriction. In the pregnant guinea pig, prenatal hypoxia during early gestation inhibits cytotrophoblast invasion of spiral arteries, increases maternal blood pressure, and induces fetal growth restriction. In this study the impact of chronic maternal hypoxia on fetal heart structure was evaluated using four-dimensional echocardiography with spatiotemporal image correlation and tomographic ultrasound, and uterine and umbilical artery resistance/pulsatility indexes and fetal heart function were evaluated using pulsed-wave Doppler ultrasound. Pregnant guinea pigs were exposed to normoxia (n = 7) or hypoxia (10.5% O2, n = 9) at 28-30 days gestation, which was maintained until full term (65 days). At full term, fetal heart structure and outflow tracts were evaluated in the four-chamber view. Fetal heart diastolic function was assessed by E wave-to-A wave diastolic filling ratios (E/A ratios) of both ventricles and systolic function by the myocardial performance index (or Tie) of left ventricles of normoxic (n = 21) and hypoxic (n = 17) fetuses. There were no structural abnormalities in fetal hearts. However, hypoxia induced asymmetric fetal growth restriction and increased the placental/fetal weight compared with normoxic controls. Hypoxia increased Doppler resistance and pulsatility indexes in the uterine, but not umbilical, arteries, had no effect on the Tie index, and increased the E/A ratio in left, but not right, ventricles. Thus, prolonged hypoxia, starting at midgestation, increases uterine artery resistance and generates fetal growth restriction at full term. Furthermore, the enhanced cardiac diastolic filling with no changes in systolic function or umbilical artery resistance suggests that the fetal guinea pig systemic circulation undergoes a compensated, adaptive response to prolonged hypoxia exposure.

Defective trophoblast invasion underlies fetal growth restriction and preeclampsia-like symptoms in the stroke-prone spontaneously hypertensive rat.

What is the impact of chronic hypertension on placental development, fetal growth and maternal outcome in the stroke-prone spontaneously hypertensive rat (SHRSP)? SHRSP showed an impaired remodeling of the spiral arteries and abnormal pattern of trophoblast invasion during placentation, which were associated with subsequent maternal glomerular injury and increased baseline hypertension as well as placental insufficiency and asymmetric fetal growth restriction (FGR). A hallmark in the pathogenesis of preeclampsia (PE) is abnormal placentation with defective remodeling of the spiral arteries preceding the onset of the maternal syndrome. Pregnancies affected by chronic hypertension display an increased risk for PE, often associated with poor maternal and fetal outcomes. However, the impact of chronic hypertension on the placentation process as well as the nature of the factors promoting the development of PE in pregnant hypertensive women remain elusive. Timed pregnancies [n = 5] were established by mating 10-12-week-old SHRSP and Wistar Kyoto (WKY, normotensive controls) females with congenic males. Maternal systolic blood pressures (SBPs) were recorded pre-mating, throughout pregnancy (GD1-19) and post-partum by the tail-cuff method. On selected dates, 24 h urine- and blood samples were collected, and animals were euthanized for isolation of implantation sites and kidneys for morphometrical analyses. The 24 h proteinuria and the albumin:creatinine ratio were used for evaluation of maternal renal function. Renal injury was assessed on periodic acid Schiff, Masson's trichrome and Sirius red stainings. Placental and fetal weights were recorded on gestation day (GD)18 and GD20, followed by determination of fetal cephalization indexes and developmental stage, according to the Witschi scale. Morphometric analyses of placental development were conducted on hematoxylin-eosin stained tissue sections collected on GD14 and GD18, and complemented with immunohistochemical evaluation of isolectin B4 binding for assessment of placental vascularization. Analyses of vascular wall alpha actin content, perforin-positive natural killer (NK) cells and cytokeratin expression by immunohistochemistry were used for evaluation of spiral artery remodeling and trophoblast invasion. SHRSP females presented significantly increased SBP records from GD13 to GD17 (SBPGD13 = 183.9 ± 3.9 mmHg, P < 0.005 versus baseline) and increased proteinuria at GD18 (P < 0.01 versus WKY). Histological examination of GD18 kidneys revealed glomerular enlargement and mesangial matrix expansion, which were not evident in pregnant WKY or age-matched virgin SHRSP. At GD20, SHRSP displayed a significant reduction of placental mass (P < 0.01 versus WKY) and signs of placental insufficiency (i.e. hypertrophy and reduced branching morphogenesis of the labyrinth layer), associated with decreased offspring weights and increased cephalization index (both P < 0.001 versus WKY) indicating asymmetric FGR. Notably, SHRSP placentas displayed an incomplete remodeling of spiral arteries starting as early as GD14, with luminal narrowing and reduced densities of perivascular NK cells followed by decreased infiltration of endovascular trophoblasts at GD18. n/a. A pitfall of the present study is the differences in the blood pressure profiles between rats and humans (i.e. unlike pregnancies affected by PE, blood pressure in SHRSP and other hypertensive rat models decreases pre-delivery), which limits extrapolation of the results. Our findings provide new insights on the role of chronic hypertension as a risk factor for PE by interfering with early events during the placentation process. The SHRSP strain represents an attractive model for further studies aimed at addressing the relative contribution of intrinsic (i.e. placental) and extrinsic (i.e. decidual/vascular) factors to defective spiral artery remodeling in pregnancies affected by PE. This work was supported by research grants from Fundación Florencio Fiorini to G.B., from Charité Stiftung to S.M.B. and University of Buenos Aires (UBACyt) to J.T. The authors have no competing interests to declare.

Modest and Severe Maternal Iron Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia in Rats

Prenatal iron-deficiency (ID) is known to alter fetal developmental trajectories, which predisposes the offspring to chronic disease in later life, although the underlying mechanisms remain unclear. Here, we sought to determine whether varying degrees of maternal anaemia could induce organ-specific patterns of hypoxia in the fetuses. Pregnant female Sprague Dawley rats were fed iron-restricted or iron-replete diets to induce a state of moderate (M-ID) or severe ID (S-ID) alongside respective controls. Ultrasound biomicroscopy was performed on gestational day (GD)20 to assess uterine and umbilical artery blood flow patterns. On GD21, tissues were collected and assessed for hypoxia using pimonidazole staining. Compared to controls, maternal haemoglobin (Hb) in M- and S-ID were reduced 17% (P < 0.01) and 48% (P < 0.001), corresponding to 39% (P < 0.001) and 65% (P < 0.001) decreases in fetal Hb. Prenatal ID caused asymmetric fetal growth restriction, which was most pronounced in S-ID. In both severities of ID, umbilical artery resistive index was increased (P < 0.01), while pulsatility index only increased in S-ID (P < 0.05). In both M-and S-ID, fetal kidneys and livers showed evidence of hypoxia (P < 0.01 vs. controls), whereas fetal brains and placentae remained normoxic. These findings indicate prenatal ID causes organ-specific fetal hypoxia, even in the absence of severe maternal anaemia.

Application of chromosomal microarray analysis in prenatal diagnosis of fetal growth restriction.

To investigate the clinical value of chromosomal microarray analysis (CMA) in the prenatal diagnosis of chromosomal abnormalities in fetal growth restriction (FGR) cases. The ultrasound findings of 107 FGR cases subjected to invasive prenatal diagnostic testing from March 2013 to October 2015 were retrospectively reviewed. Karyotyping was performed in all cases, and CMA was performed in 80 cases. In our study, karyotype analysis identified chromosomal aberrations in 9.3% (10/107) of the cases, while CMA detected abnormalities in 18.8% (15/80) of the cases. CMA achieved a 11.4% detection rate of chromosomal abnormalities among FGR cases with a normal karyotype. Among 53 FGR cases without malformations, CMA increased (9.4%; 95%CI, 1.6%-17.3%) the detection rate of chromosomal abnormalities. CMA identified more chromosomal abnormalities (50.0%; 95%CI, 19.0%-81.0%) than karyotyping (30.0%; 95%CI, 7.0%-65.0%) among the cases diagnosed during the second trimester. Further, the detection rate in cases with asymmetric FGR was higher with CMA (33.3%; 95%CI, 10.0%-65.0%) than with karyotyping (16.7 %; 95%CI, 2.0%-48.0%). Our study highlights the added value of CMA compared with karyotyping in evaluation of asymmetric FGR cases diagnosed during the second trimester without sonographic anomalies. © 2016 John Wiley & Sons, Ltd.

Effect of l-Arginine on Nitric Oxide Levels in Intrauterine Growth Restriction and its Correlation with Fetal Outcome.

The current management of intrauterine growth restriction (IUGR) being empirical and aimed at selecting a safe time for delivery. Acknowledging the beneficial effects of l-arginine on endothelial vasculature the present study was designed to evaluate efficacy of l-arginine on bioavailability of nitric oxide (NO) with respect to fetal outcome. With l-arginine supplementation, mean NO levels were significantly increased and a significant mild reduction in systolic/end-diastolic velocity ratio (S/D ratio) was observed on doppler blood flow study, also neonatal outcome improved and incidences of complications were lowered. A deficiency in NO may play an important role in the causation of asymmetric fetal growth restriction. l-Arginine can be used to increase maternal NO levels, enhancing birth weight and decreasing neonatal morbidity. The ideal candidate for arginine therapy according to our study would be IUGR cases with S/D ratio less than 4.96±0.49 and NO levels below 33μmol/L with minimum of 3weeks duration of arginine supplementation.

188: The effect of orthostatic stress on brain sparing phenomena in asymmetrical and symmetrical fetal growth restriction

188: The effect of orthostatic stress on brain sparing phenomena in asymmetrical and symmetrical fetal growth restriction

Gestational Hypoxia Induces Preeclampsia-Like Symptoms via Heightened Endothelin-1 Signaling in Pregnant Rats

Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 ± 6.1 versus 138.5 ± 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 ± 4.6 versus 125.1 ± 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10 ± 0.01 versus 0.20 ± 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.