Treatment of parathormone-dependent hypercalcaemia in the third-trimester of pregnancy.

Not required for Clinical Vignette.

Perinatal features of children with Silver-Russell syndrome due to 11p15 loss of methylation.

Background: A diagnosis of Silver-Russell syndrome (SRS), a rare imprinting disorder responsible for foetal growth restriction, is considered for patients presenting at least four criteria of the Netchine-Harbison clinical scoring system (NH-CSS). Certain items of the NH-CSS are not assessable until the age of 2 years. The objective was to determine perinatal characteristics of children with SRS to allow an early diagnosis. Methods: We retrospectively compared the perinatal characteristics of children with SRS (n = 17) with those of newborns small for gestational age (SGA) due to placental insufficiency (PI) (n = 21). Results: Children with SRS showed earlier and more severely altered foetal biometry than SGA newborns due to PI. Twenty-three percent of patients with SRS showed uterine artery Doppler anomalies. SRS children were significantly smaller at birth (birth length <-3 SDS in 77% of cases in the SRS group vs. 15% in the PI group, p = 0.0001). Conclusion: The diagnosis of SRS must be evoked in the neonatal period for SGA newborns with a growth delay present from the second trimester of pregnancy, a birth length <-3 SDS and a relative macrocephaly. Doppler anomalies, classically used to orient the cause of SGA towards PI, did not rule out the diagnosis of SRS.

Reduced T2*-weighted placental MRI predicts foetal growth restriction in women with chronic rheumatic disease-a Danish explorative study.

OBJECTIVES: Women with chronic rheumatic disease (CRD) are at greater risk of foetal growth restriction than their healthy peers. T2*-weighted magnetic resonance imaging of placenta (T2*P-MRI) is superior to conventional ultrasonography in predicting birth weight and works as a proxy metabolic mirror of the placental function. We aimed to compare T2*P-MRI in pregnant women with CRD and healthy controls. In addition, we aimed to investigate the correlation between T2*P-MRI and birth weight. METHODS: Using a General Electric (GE) 1.5 Tesla, we consecutively performed T2*-weighted placental MRI in 10 women with CRD and 18 healthy controls at gestational week (GW)24 and GW32. We prospectively collected clinical parameters during pregnancy including birth outcome and placental weight. RESULTS: Women with CRD had significantly lower T2*P-MRI values at GW24 than healthy controls (median T2*(IQR) 92.1 ms (81.6; 122.4) versus 118.6 ms (105.1; 129.1), p = 0.03). T2*P-MRI values at GW24 showed a significant correlation with birth weight, as the T2*P-MRI value was reduced in all four pregnancies complicated by SGA at birth. Three out of four pregnancies complicated by SGA at birth remained undetected by routine antenatal ultrasound. CONCLUSION: This study demonstrates reduced T2*P-MRI values and a high proportion of SGA at birth in CRD pregnancies compared to controls, suggesting an increased risk of placental dysfunction in CRD pregnancies. T2*P-MRI may have the potential to focus clinical vigilance by identifying pregnancies at risk of SGA as early as GW24. Key Points • Placenta-related causes of foetal growth restriction in women with rheumatic disease remain to be investigated. • T2*P-MRI values at gestational week 24 predicted foetuses small for gestational age at birth. • T2*P-MRI may indicate pregnant women with chronic rheumatic disease (CRD) in need of treatment optimization.

Mitochondrial quality control alterations and placenta-related disorders.

Mitochondria are ubiquitous in eukaryotic cells. Normal maintenance of function is the premise and basis for various physiological activities. Mitochondrial dysfunction is commonly observed in a wide range of pathological conditions, such as neurodegenerative, metabolic, cardiovascular, and various diseases related to foetal growth and development. The placenta is a highly energy-dependent organ that acts as an intermediary between the mother and foetus and functions to maintain foetal growth and development. Recent studies have demonstrated that mitochondrial dysfunction is associated with placental disorders. Defects in mitochondrial quality control mechanisms may lead to preeclampsia and foetal growth restriction. In this review, we address the quality control mechanisms of mitochondria and the relevant pathologies of mitochondrial dysfunction in placenta-related diseases, such as preeclampsia and foetal growth restriction. This review also investigates the relation between mitochondrial dysfunction and placental disorders.

Association between small-for-gestational age and poor school performance in 2 500 000 children born 1973-2002.

AIM: To examine the association between infant weight for gestational age and school performance when leaving school at 16 years of age. METHODS: Out of 2 525 571 infants born near- or at term, between 1 January 1973 and 31 December 2002, identified from the Swedish Medical Birth Register, 65 912 (2.6%) were born small-for-gestational age (SGA). Outcomes studied were the risk for the need for education in special school, and the final average grades. Modified Poisson regression analyses and weighted linear regression analyses were performed. RESULTS: An association between SGA and the need for a special school was found, irrespective of restrictions or adjustments (RR between 2.47 and 2.25). SGA was associated with final grades below the 10th and 25th percentile (RR 1.49 and 1.18, respectively). A linear relationship between maternal height and the RR for education in special school (p = 0.005), suggested that SGA is a stronger risk factor among children of tall than of shorter women. CONCLUSION: SGA increased the risk for poor school performance, and for the need for a special school. We found an association between maternal height and school performance in relation to birthweight, suggesting that maternal height should be considered when estimating the impact of SGA on later outcomes.

Angiogenic growth factors, oxidative stress and haematobiochemical measures as predictors of preeclampsia with and without foetal growth restriction: A case-control study in a Ghanaian population.

INTRODUCTION: This study compares the angiogenic growth mediators (AGMs), oxidative stress (OS) and haematobiochemical profile as well as foeto-maternal outcomes of preeclampsia (PE) with and without foetal growth restriction (FGR) and the discriminative potential of these markers for identifying these conditions. METHODS: This hospital-based case-control study recruited a total of 209 women including 109 PE women without FGR and 48 PE women with FGR as cases whereas 52 normotensive pregnant women were recruited as controls. OS and AGMs and haematobiochemical markers were measured for all participants. RESULTS: The rates of foetal complications including intrauterine foetal death and foetal distress were more common in PE with FGR than PE without FGR (p < 0.05) but maternal complications were comparable across these groups (p > 0.05). Of the haematobiochemical markers, placental growth factors (PIGF), PIGF/8-Isoprostane, sFlt-1/PIGF (AUC = 0.87, p < 0.001), soluble FMS-tyrosine kinase receptor-1 (sFlt-1) (AUC = 0.85, p < 0.001), total antioxidant capacity, 8-isoprostane (AUC = 0.83, p < 0.001) and lactate dehydrogenase (AUC = 0.70, p < 0.001) were more associated and showed at least an acceptable discrimination for PE with FGR against PE only. DISCUSSION: The occurrence of FGR in PE patients does not necessarily indicate a severe maternal presentation of the condition but a tendency for adverse foetal outcomes. Cumulative assessment of OS and AGMs may provide diagnostic usefulness for distinguishing PE with and without FGR.

The head circumference to chest circumference ratio provided an easy way to detect foetal growth restriction in term infants.

AIM: The head circumference to chest circumference (HC/CC) ratio has been used to identify low birth weight infants in developed countries. This study was conducted to examine whether the ratio could distinguish asymmetrical foetal growth restriction (FGR). METHODS: This retrospective observational study was conducted with 1955 infants (50.5% male) born at term between 2016 and 2020 at Tokyo Metropolitan Toshima Hospital, Japan. RESULTS: We found that 120 (6.1%) had FGR. Their mean birth weight was 3052.1 ± 367.3 g, and their mean gestational age was 39.1 ± 1.1 weeks. Logistic regression analysis showed that the association between the HC/CC ratio and FGR had a regression coefficient of -20.6 (p < 0.000). The linear regression analysis showed that the association between the HC/CC ratio and the birth weight z-score had a regression coefficient of -8.59 (p < 0.000). The coefficient of correlation was -0.33 (p < 0.001). The receiver operating characteristic curve for detecting FGR showed that the area under the curve was 0.75 and the cut-off value was 0.93, with sensitivity of 75.8% and specificity of 60.8%. CONCLUSION: Our study established the associations between HC/CC ratio and FGR and birth weight z-scores and confirmed that the ratio provided an easy way to detect FGR in term-born infants.

Human placental vascular and perivascular cell heterogeneity differs between first trimester and term, and in pregnancies affected by foetal growth restriction.

Growth-restricted placentae have a reduced vascular network, impairing exchange of nutrients and oxygen. However, little is known about the differentiation events and cell types that underpin normal/abnormal placental vascular formation and function. Here, we used 23-colour flow cytometry to characterize placental vascular/perivascular populations between first trimester and term, and in foetal growth restriction (FGR). First-trimester endothelial cells had an immature phenotype (CD144+/lowCD36-CD146low), while term endothelial cells expressed mature endothelial markers (CD36+CD146+). At term, a distinct population of CD31low endothelial cells co-expressed mesenchymal markers (CD90, CD26), indicating a capacity for endothelial to mesenchymal transition (EndMT). In FGR, compared with normal pregnancies, endothelial cells constituted 3-fold fewer villous core cells (P < 0.05), contributing to an increased perivascular: endothelial cell ratio (2.6-fold, P < 0.05). This suggests that abnormal EndMT may play a role in FGR. First-trimester endothelial cells underwent EndMT in culture, losing endothelial (CD31, CD34, CD144) and gaining mesenchymal (CD90, CD26) marker expression. Together this highlights how differences in villous core cell heterogeneity and phenotype may contribute to FGR pathophysiology across gestation.

Successful Pregnancy Outcome in an Operated Case of Budd-Chiari Syndrome Having Fetal Growth Restriction: A Twisted Tale of Gravid.

Budd-Chiari Syndrome (BCS) primarily affects women in the reproductive age group, with an ever-increasing incidence in the general population. Due to its rarity, it is not known precisely how a pregnancy progresses in a woman with BCS and what can happen to the baby. A rare condition known as Budd-Chiari syndrome causes the hepatic veins in the liver to constrict and become blocked. The challenges in pregnancy, such as decreasing hepatic function, a rise in thrombotic and bleeding events, or ascites, have historically made pregnancy inappropriate in these people. Here, we present a case of an unbooked 24-year-old female, a known case of treated BCS with 36 weeks and three days gestation period. She was referred from a peripheral hospital to our hospital's emergency department because of having fetal growth restriction. By presenting this rare case, we expect more extensive studies will be conducted on the effect of pregnancy on BCS and the effect of BCS on pregnancy which will help obstetricians to turn this rare possibility of conception into a fair possibility.

Matrix metalloproteinase-3 in preeclamptic and normotensive pregnancies complicated by foetal growth restriction.

The aim of the present study was to assess the interrelationships between the level of matrix metalloproteinase-3 in the blood serum of pregnant women and the occurrence of pregnancy complications in the form of foetal growth restriction, idiopathic or in the course of preeclampsia. Methods: A total of 245 patients were included in the study. 65 of them are normotensive patients with idiopathic foetal growth restriction (FGR group). 115 women were diagnosed with severe preeclampsia. In the group of women with preeclampsia, there were 51 patients with adequate for gestational age foetal growth and 64 patients with the foetal growth restriction in the course of severe preeclampsia. The control group consisted of 65 healthy patients with normal pregnancy course, with no cardiovascular disorders at the present and in the history, normal blood pressure and normal intrauterine foetal growth. Matrix metalloproteinase-3 (MMP-3) in maternal circulation were determined by ELISA method. Results: In our studies, we observed elevated levels of matrix metalloproteinase-3 in preeclamptic women with pregnancies complicated by FGR and significantly lower in the group of normotensive women with idiopathic FGR. The mean values of MMP-3 were 33.50 ± 65.74 ng/mL [Median (min-max) 19.19 (2.05-454.53)] in the Control group, 21.22 ± 23.28 ng/mL [Median (min-max) 16.39 (3.45-156.29)] in the FGR group, 35.96 ± 46.14 ng/mL [Median (min-max) 25.21 (4.16-253.05)] in the P group and 52.81 ± 61.61 ng/mL [Median (min-max) 32.83 (5.06-314.14)] in preeclamptic women with FGR (group PI) respectively.The assessment of MMP-3 in the serum of women with pregnancies complicated by intrauterine foetal growth restriction with normal values of blood pressure and in the group of preeclamptic patients in relation to healthy pregnant women with uncomplicated pregnancies and in relation to preeclamptic patients with normal intrauterine foetal growth is the novelty of this study. Such a strict definition of each research group seems to allow for the assessment of each pregnancy complication separately. Conclusion: It seems that higher levels of MMP-3 in preeclamptic women may suggest the need for observation towards the risk of lower birth weight of newborns. This necessitates further research and a better integration in the clinical practice.

Risk Factors Associated With Intrauterine Growth Restriction: A Case-Control Study.

Background Intrauterine growth restriction (IUGR) is a disorder in which the fetus fails to reach its genetic development potential and is considered to be present when the weight at birth is less than the 10th percentile; as a result, it is at risk of increased postnatal morbidity and mortality. Every year, approximately 24% of newborns worldwide are determined to have IUGR. The objective of the present study was to identify various sociodemographic, medical, and obstetric risk factors associated with IUGR. Methodology A case-control study was conducted from January 2020 to December 2022. Fifty-four cases and 54 controls were included in the study. Postnatal women with neonates having birth weight below the 10th percentile for gestational age (GA) were recruited as cases in the study. Control cases were postnatal women with neonatal birth weight appropriate for (GA). Detailed history with respect to socio-demographic, medical, and obstetric parameters was noted and compared. Results Among the sociodemographic factors, only socioeconomic status showed significant statistical differences with the age group of 21 to 25 years showing maximum (51.9%) IUGR cases. Among the maternal risk factors, anemia (29.6%) and hypertensive disorders of pregnancy (22.2%) were marked as significant risk factors for IUGR. There was no significant difference in the distribution of past medical and obstetric histories between the two research groups. Conclusion Due to the poor living conditions, low literacy rates, and general lack of knowledge, low socioeconomic level increases the risk of IUGR. This leads to nutritional deficiencies and insufficient growth environment which results in anemia and hypertensive disorders of pregnancy which are potent risk factors for IUGR. IUGR may be caused by maternal risk factors as well as past medical and obstetric conditions. However, for the risk factor of IUGR, the birth weight at the time of delivery could be taken into consideration as well.

Neurodevelopmental outcomes of very preterm infants born following early foetal growth restriction with absent end-diastolic umbilical flow.

This study aims to assess the impact of time of onset and features of early foetal growth restriction (FGR) with absent end-diastolic flow (AEDF) on pregnancy outcomes and on preterm infants' clinical and neurodevelopmental outcomes up to 2 years corrected age. This is a retrospective, cohort study led at a level IV Obstetric and Neonatal Unit in Bologna, Italy. Pregnant women were eligible if having singleton pregnancies, with no major foetal anomaly detected, and diagnosed with early FGR + AEDF (defined as FGR + AEDF detected before 32 weeks gestation). Early FGR + AEDF was further classified according to time of onset and specific features into very early and persistent (VEP, FGR + AEDF first detected at 20-24 weeks gestation and persistent at the following scans), very early but transient (VET, FGR + AEDF detected at 20-24 weeks gestation and progressively improving at the following scans) and later (LA, FGR + AEDF detected between 25 and 32 weeks gestation). Pregnancy and neonatal outcomes and infant follow-up data were collected and compared among groups. Neurodevelopment was assessed using the revised Griffiths Mental Developmental Scales (GMDS-R) 0-2 years. A regression analysis was performed to identify early predictors of preterm infants' neurodevelopmental impairment. Fifty-two pregnant women with an antenatal diagnosis of early FGR + AEDF were included in the study (16 VEP, 14 VET, 22 LA). Four intrauterine foetal deaths occurred, all in the VEP group (p = 0.010). Compared to LA infants, VEP infants were born with lower gestational age and lower birth weight, had lower arterial cord blood pH and were at higher risk for intraventricular haemorrhage and periventricular leukomalacia (p < 0.05 for all comparisons). At 12 months, VEP infants had worse GMDS-R scores, both in the general quotient (mean [SD] 91.8 [12.4] vs 104.6 [8.7] in LA) and in the performance domain (mean [SD] 93.3 [15.4] vs 108.8 [8.8] in LA). This latter difference persisted at 24 months (mean [SD] 68.3 [17.0] vs 92.9 [17.7] in LA). In multivariate analysis, at 12 months corrected age, PVL was found to be an independent predictor of impaired general quotient, while the features and timing of antenatal Doppler alterations predicted worse scores in the performance domain.   Conclusion: Timing of onset and features of early FGR + AEDF might impact differently on neonatal clinical and neurodevelopmental outcomes. Shared awareness of the importance of FGR + AEDF features between obstetricians and neonatologists may offer valuable tools for antenatal counselling and for tailoring pregnancy management and neonatal follow-up in light of specific antenatal and neonatal risk factors. What is Known: • Foetal growth restriction (FGR), together with antenatal umbilical Doppler abnormalities, is known to affect maternal and neonatal outcomes. • Infants born preterm and growth-restricted face the highest risk for neurodevelopmental impairment, especially when FGR occurs early during pregnancy (early FGR, before 32 weeks gestation). What is New: • The timing of onset and features of FGR and antenatal umbilical Doppler abnormalities impact differently on maternal and neonatal outcomes; when FGR and Doppler abnormalities occur very early, at the limit of neonatal viability, and persist until delivery, infants face the highest risk for neurodevelopmental impairment. • Shared knowledge between obstetricians and neonatologists about timing of onset and features of FGR would provide a valuable tool for informed antenatal counselling in high-risk pregnancies.

Integrated growth assessment in the first 1000 d of life: an interdisciplinary conceptual framework.

OBJECTIVES: Prenatal growth affects short- and long-term morbidity, mortality and growth, yet communication between prenatal and postnatal healthcare teams is often minimal. This paper aims to develop an integrated, interdisciplinary framework for foetal/infant growth assessment, contributing to the continuity of care across the first 1000 d of life. DESIGN: A multidisciplinary think-tank met regularly over many months to share and debate their practice and research experience related to foetal/infant growth assessment. Participants' personal practice and knowledge were verified against and supplemented by published research. SETTING: Online and in-person brainstorming sessions of growth assessment practices that are feasible and valuable in resource-limited, low- and middle-income country (LMIC) settings. PARTICIPANTS: A group of obstetricians, paediatricians, dietitians/nutritionists and a statistician. RESULTS: Numerous measurements, indices and indicators were identified for growth assessment in the first 1000 d. Relationships between foetal, neonatal and infant measurements were elucidated and integrated into an interdisciplinary framework. Practices relevant to LMIC were then highlighted: antenatal Doppler screening, comprehensive and accurate birth anthropometry (including proportionality of weight, length and head circumference), placenta weighing and incorporation of length-for-age, weight-for-length and mid-upper arm circumference in routine growth monitoring. The need for appropriate, standardised clinical records and corresponding policies to guide clinical practice and facilitate interdisciplinary communication over time became apparent. CONCLUSIONS: Clearer communication between prenatal, perinatal and postnatal health care providers, within the framework of a common understanding of growth assessment and a supportive policy environment, is a prerequisite to continuity of care and optimal health and development outcomes.

Vitamin D in pregnancy (GRAVITD) - a randomised controlled trial identifying associations and mechanisms linking maternal Vitamin D deficiency to placental dysfunction and adverse pregnancy outcomes - study protocol.

BACKGROUND: The prevalence of vitamin D deficiency is high among pregnant women. Vitamin D deficiency in pregnancy is associated with increased risk of adverse pregnancy outcomes especially complications related to placental dysfunction and insulin resistance. The objective of this study is to investigate if a higher dose of vitamin D supplementation in pregnancy reduces the prevalence of vitamin D deficiency and prevents adverse pregnancy outcome with special emphasize on preeclampsia, foetal growth restriction and gestational diabetes. METHODS: GRAVITD is a double-blinded randomised trial with parallel groups where all pregnant women attending the free of charge national nuchal translucency scan programme in gestational week 10-14 at Randers Regional Hospital are invited to participate. Enrolment started in June 2020. Participants are randomised in a two armed randomization with a 1:1 allocation ratio into 1) control group - receives 10 µg of vitamin D or 2) intervention group - receives 90 µg of vitamin D. A total of 2000 pregnant women will be included. Maternal blood samples and questionnaires describing life-style habits are collected upon enrolment. For half of the participants blood samples and questionnaires will be repeated again in 3rd trimester. Blood samples will be analysed for 25-hydroxy-vitamin D using high-performance liquid chromatography coupled with tandem mass spectrometry. Upon delivery, placental tissue and umbilicalcord blood will be collected and information on maternal and fetal outcomes will be exstracted from medical records. The primary outcomes are serum levels of 25-hydroxy-vitamin D ≥ 75 nmol/L and the rate of preeclampsia, foetal growth restriction and gestational diabetes. Secondary outcome includes identification and impact on placental functions related to vitamin D. A tertiary outcome is to initiate a cohort of children born from mothers in the trial for future follow-up of the effects of vitamin D on childhood health. DISCUSSION: Provided that this trial finds beneficial effects of a higher dose of vitamin D supplementation in pregnancies, official recommendations can be adjusted accordingly. This will provide a low-cost and easily implementable adjustment of prenatal care which can improve health for both mother and child during pregnancy and beyond. TRIAL REGISTRATION: ClinicalTrial.gov: NCT04291313 . Registered February 17, 2020.

Epigenetic control of the imprinted growth regulator Cdkn1c in cadmium-induced placental dysfunction.

Cadmium (Cd) is a toxic metal ubiquitous in the environment. In utero, Cd is inefficiently transported to the foetus but causes foetal growth restriction (FGR), likely through impairment of the placenta where Cd accumulates. However, the underlying molecular mechanisms are poorly understood. Cd can modulate the expression of imprinted genes, defined by their transcription from one parental allele, which play critical roles in placental and foetal growth. The expression of imprinted genes is governed by DNA methylation at Imprinting Control Regions (ICRs), which are susceptible to environmental perturbation. The imprinted gene Cdkn1c/CDKN1C is a major regulator of placental development, is implicated in FGR, and shows increased expression in response to Cd exposure in mice. Here, we use a hybrid mouse model of in utero Cd exposure to determine if the increase in placental Cdkn1c expression is caused by changes to ICR DNA methylation and loss of imprinting (LOI). Consistent with prior studies, Cd causes FGR and impacts placental structure and Cdkn1c expression at late gestation. Using polymorphisms to distinguish parental alleles, we demonstrate that increased Cdkn1c expression is not driven by changes to DNA methylation or LOI. We show that Cdkn1c is expressed primarily in the placental labyrinth which is proportionally increased in size in response to Cd. We conclude that the Cd-associated increase in Cdkn1c expression can be fully explained by alterations to placental structure. These results have implications for understanding mechanisms of Cd-induced placental dysfunction and, more broadly, for the study of FGR associated with increased Cdkn1c/CDKN1C expression.

Risk factors and foetal growth restriction associated with expectant treatment of early-onset preeclampsia.

OBJECTIVE: To identify the factors affecting expectant management of early-onset preeclampsia, and evaluate the correlation between expectant treatment and foetal growth restriction. MATERIALS AND METHODS: The retrospective study included 72 women who were admitted for early-onset preeclampsia between February 2018 to April 2021. Data included maternal clinical parameters, demographic and maternal and neonatal outcomes, which were analysed for correlation. RESULTS: Multiple logistic regression analysis demonstrated that the time interval from the onset of 24-h proteinuria to termination of pregnancy showed a strong correlation with the expectant treatment; Univariate logistic analysis confirmed that there was no correlation between expectant treatment and foetal growth restriction. CONCLUSION: There was a negative correlation between the duration of 24-h proteinuria and the expectant treatment of patients with early-onset preeclampsia; Expectant treatment could not improve the development of foetal growth restriction in patients with early-onset preeclampsia.KEY MESSAGESThe duration of 24-h proteinuria affects the effectiveness of expectant management of early-onset preeclampsia.Expectant management can reduce adverse neonatal outcomes due to iatrogenic preterm delivery, but it cannot improve the occurrence of foetal growth restriction.

Comparative Study of the Umbilical Artery Doppler Indices of Healthy and Growth-Restricted Foetuses in Lagos.

Aim of the Study: This study compared the umbilical artery Doppler indices (UADI) in normal and foetal growth-restricted (FGR) foetuses to determine the relationship between the UADI and pregnancy outcomes. Materials and Methods: This was a case-control study that recruited one hundred and eighty pregnant women comprising 90 with FGR pregnancies and 90 with normal pregnancies. Foetal biometric parameters and UADI were measured in all the participants. The UADI and clinical outcomes (preterm delivery, birth weight, perinatal death, etc.) of the normal and FGR foetuses were compared. Results: The mean estimated foetal weights of the FGR pregnancies (subjects) and normal pregnancies (controls) were 2.76 ± 0.66 kg and 3.62 ± 0.37 kg, respectively (P < 0.0001). The mean APGAR score at 5 min was 6.93 ± 1.72 for subjects and 8.03 ± 0.94 for controls (P < 0.0001). Abnormal umbilical artery Doppler waveforms were detected: decreased end-diastolic flow in 25 (27.8%), absent end-diastolic in 7 (7.8%) and reversed end-diastolic flow in 4 (4.4%) of the FGR pregnancies. There were 74 (82.2%) preterm deliveries among the subjects, while only 7 (7.8%) of the controls had preterm deliveries. Six deaths (two perinatal and four neonatal deaths) were recorded among the subjects, while no death occurred among the controls. Conclusion: Foetuses with FGR showed significantly higher quantitative Doppler indices (increased RI, PI, SD ratio), and a higher prevalence of abnormal umbilical artery waveform pattern (qualitative) than the healthy foetuses (controls).

Hyperactivation of Wnt/ß-catenin and Jak/Stat3 pathways in human and zebrafish foetal growth restriction models: Implications for pharmacological rescue.

Foetal Growth Restriction (FGR), previously known as Intrauterine Growth Restriction (IUGR), is an obstetrical condition due to placental insufficiency, affecting yearly about 30 million newborns worldwide. In this work, we aimed to identify and pharmacologically target signalling pathways specifically involved in the FGR condition, focusing on FGR-related cardiovascular phenotypes. The transcriptional profile of human umbilical cords from FGR and control cases was compared with the response to hypoxia of zebrafish (Danio rerio) transgenic lines reporting in vivo the activity of twelve signalling pathways involved in embryonic development. Wnt/ß-catenin and Jak/Stat3 were found as key pathways significantly dysregulated in both human and zebrafish samples. This information was used in a chemical-genetic analysis to test drugs targeting Wnt/ß-catenin and Jak/Stat3 pathways to rescue a set of FGR phenotypes, including growth restriction and cardiovascular modifications. Treatments with the Wnt/ß-catenin agonist SB216763 successfully rescued body dimensions, cardiac shape, and vessel organization in zebrafish FGR models. Our data support the Wnt/ß-catenin pathway as a key FGR marker and a promising target for pharmacological intervention in the FGR condition.

Pre-pregnancy check-up of maternal vascular status and associated phenotype is crucial for the health of mother and offspring.

Abstract: Cardiovascular disease remains the leading cause of disease burden globally with far-reaching consequences including enormous socio-economic burden to healthcare and society at large. Cardiovascular health is decisive for reproductive function, healthy pregnancy and postpartum. During pregnancy, maternal cardiovascular system is exposed to highly increased haemodynamic stress that significantly impacts health status of the mother and offspring. Resulting from sub-optimal maternal health conditions overlooked in pre-pregnancy time, progressive abnormalities can be expected during pregnancy and postpartum. Contextually, there are two main concepts to follow in the framework of predictive, preventive and personalised medicine, namely to develop:1. advanced screening of sub-optimal health conditions in young populations to predict and prevent individual health risks prior to planned pregnancies2. in-depth companion diagnostics during pregnancy to predict and prevent long-lasting postpartum health risks of the mother and offspring.Data collected in the current study demonstrate group-specific complications to health of the mother and offspring and clinical relevance of the related phenotyping in pre-pregnant mothers. Diagnostic approach proposed in this study revealed its great clinical utility demonstrating important synergies between cardiovascular maladaptation and connective tissue dysfunction. Co-diagnosed pre-pregnancy low BMI of the mother, connective tissue dysfunction, increased stiffness of peripheral vessels and decreased blood pressure are considered a highly specific maternal phenotype useful for innovative screening programmes in young populations to predict and prevent severe risks to health of the mother and offspring. This crucial discovery brings together systemic effects characteristic, for example, for individuals with Flammer syndrome predisposed to the phenotype-specific primary vascular dysregulation, pregnancy-associated risks, normal tension glaucoma, ischemic stroke at young age, impaired wound healing and associated disorders. Proposed maternal phenotyping is crucial to predict and effectively protect both the mother and offspring against health-to-disease transition. Pre-pregnancy check-up focused on sub-optimal health and utilising here described phenotypes is pivotal for advanced health policy. Plain English abstract: Cardiovascular health is decisive for reproductive function and healthy pregnancy. During pregnancy, maternal cardiovascular system may demonstrate health-to-disease transition relevant for the affected mother and offspring. Overlooked in pre-pregnancy time, progressive abnormalities can be expected during pregnancy and lifelong. Here we co-diagnosed maternal pre-pregnancy low bodyweight with systemic effects which may increase risks of pregnancy, eye and heart disorders and ischemic stroke at young age, amongst others. Innovative screening  programmes focused on sub-optimal health in young populations to predict and to mitigate individual health risks prior to pregnancy is an essential innovation for health policy proposed.

Preventing antenatal stillbirths: An innovative approach for primary health care.

BACKGROUND: In South Africa (SA), approximately 16 000 stillbirths occur annually. Most are classified as unexplained and occur in district hospitals. Many of these deaths may be caused by undetected foetal growth restriction. Continuous wave Doppler ultrasound of the umbilical artery (CWDU-UmA) is a simple method for assessing placental function. This screening method may detect the foetus at risk of dying and growth-restricted foetuses, allowing for appropriate management. METHODS: A cohort study was conducted across South Africa. Pregnant women attending primary health care clinics at 28-34 weeks gestation were screened using CWDU-UmA. Women not screened at those antenatal clinics served as control group 1. Control group 2 consisted of the subset of control group 1 with women detected with antenatal complications excluded. Women with foetuses identified with an abnormal CWDU-UmA test were referred and managed according to a standardised protocol. A comparison between the study and control groups was performed. RESULTS: The study group consisted of 6536 pregnancies, and there were 66 stillbirths (stillbirth rate [SBR]: 10.1/1000 births). In control group 1, there were 193 stillbirths in 10 832 women (SBR: 17.8/1000 births), and in control group 2, 152 stillbirths in 9811 women (SBR: 15.5/1000 births) (risk ratio: 0.57, 95% confidence intervals: 0.29-0.85 and 0.65, 0.36-0.94, respectively). CONCLUSION: Screening a low-risk pregnant population identified the low-risk mother with a high-risk foetus, and acting on the information as described was associated with a significant reduction (35% - 43%) in stillbirths. This demonstrates a step-change reduction in stillbirths and warrants screening in SA.