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.

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.

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.

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.

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.

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.

Associations of preterm birth, small-for-gestational age, preeclampsia and placental abruption with attention-deficit/hyperactivity disorder in the offspring: Nationwide cohort and sibling-controlled studies.

AIM: The aim of this study was to investigate preterm birth, small-for-gestational age (SGA), preeclampsia and placental abruption in relation to attention-deficit/hyperactivity disorder (ADHD) in offspring. METHODS: We conducted a population-based cohort study among non-malformed live-born singleton children in Sweden born during 2002-2014. Using national registries with recorded information, we followed 1,212,201 children for an ADHD diagnosis from 3 to 15 years. We compared ADHD rates between exposure categories using adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox proportional hazards models. We also conducted sibling-controlled analyses among 751,464 full siblings. RESULTS: There were 27,665 ADHD diagnoses in the cohort. Compared with term birth (≥37 weeks), adjusted HR (95% CI) for ADHD increased with decreasing gestational age: 1.18 (1.11, 1.25), 1.61 (1.37, 1.89) and 2.79 (2.23, 3.49) for 32-36 weeks, 28-31 weeks and 22-27 weeks. Both spontaneous and medically indicated preterm birth were associated with ADHD. SGA was related to 1.62 (1.49, 1.77) times higher ADHD incidence. Preeclampsia, but not placental abruption, was associated with ADHD. Sibling-controlled analyses showed similar results. Preterm birth did not fully explain the associations of SGA or preeclampsia with ADHD. CONCLUSION: Preterm birth, SGA and preeclampsia are related to ADHD incidence in offspring.

Antenatal and neonatal risk factors in very preterm children were associated with language difficulties at 9 years of age.

AIM: This Finnish study compared language and reading abilities between schoolchildren born at a very low gestational age (VLGA) of <32 weeks and at term and analysed any associations between antenatal and neonatal risk factors and language skills in the VLGA group. METHODS: We prospectively followed 76 children born at a VLGA and 50 children born at term when they reached a mean age of 9.0 (8.1-10.0) years. They attended mainstream schools and had no severe neurosensory disabilities. Receptive language ability, rapid naming and word reading were evaluated using standardised tests. RESULTS: Children in the VLGA group had lower scores for receptive language abilities (median 55.0 vs. 57.0, p = 0.01) and word reading (mean 4.4 vs. 5.1, p = 0.03) than the children in the term group. In the VLGA group, foetal growth restriction was associated with lower scores for rapid naming, early intraventricular haemorrhage was associated with poor word reading and respiratory distress syndrome was associated with poor rapid naming (p < 0.05). CONCLUSION: Schoolchildren born at a VLGA had more difficulties with receptive language abilities and word reading than children born at term. Foetal growth restriction and early neonatal morbidities were associated with language difficulties.

Umbilical cord diameter in the prediction of foetal growth restriction: a cross sectional study.

This was a cross sectional study with a prospective design conducted from October 2018 to October 2019. We recruited patients at risk for FGR and normal pregnant women. Each patient had ultrasound examination for the umbilical cord diameter in the 28th, 32nd, 36th, and the 40th week, Foetal growth restriction developed in 10/76 (13.2%) patients in the at risk group. The umbilical cord diameter was significantly lower in the at risk group (1.8 ± 0.2 versus 2.0 ± 0.2 in the control group with a p value of <.001). The umbilical cord diameter was highly predictive for the occurrence of FGR at each antenatal care visit as well as at delivery. We concluded that the umbilical cord diameter was a significant predictor of foetal growth restriction when applied through the antenatal care visits. It is a simple and easy method causing no distress for the patients.IMPACT STATEMENTWhat is already known on this subject? Conflicting results exist regarding the predictive role of the umbilical cord in foetal growth restriction.What do the results of this study add? Foetal umbilical cord diameter was correlated significantly to foetal weight and had a significant predictive role in the prediction of FGR. The cut off values for the umbilical cord diameter in women with FGR were not evaluated before.What are the implications of these findings for clinical practice and/or further research? Comparing the ultrasound findings with histopathologic examination of the umbilical cord and the placentas would be recommended.

Relationship between second-trimester amniotic fluid and plasma levels of angiopoietin-2 and thrombomodulin with adverse pregnancy outcome.

Our objective is to investigate maternal midtrimester plasma and amniotic fluid (AF) levels of angiopoietin-2 (Ang-2) and thrombomodulin (TM), which are involved in vascular remodelling and endothelium activation, in placental disorders including foetal growth restriction (FGR) and preeclampsia (PE). This prospective multiparametric pilot study was conducted at the Perinatology Division of Trakya University in a population undergoing genetic amniocentesis. Both AF and plasma aliquots were kept in -80 °C until ELISA assay. The pregnancies were followed up until the end of gestation in terms of obstetric results. Amniotic fluid and plasma aliquots from 127 pregnancies who underwent genetic amniocentesis between 16 and 24 weeks of gestation were analysed. During the final data evaluation, 39 were excluded with various reasons. Twelve subsequently developed FGR and 11 complicated with PE. The control group (n = 65) was consisted of women delivered >37th week with an uncomplicated outcome. The midtrimester maternal Ang-2 levels in both AF and plasma and also TM levels in plasma were found to be significantly increased in pregnancies who subsequently developed FGR or PE (p< .05). The midtrimester Ang-2, which rises in both plasma and AF and the midtrimester TM, which only significantly increase in plasma compartment in PE group, as compensatory mechanism may be the precursors of placental disorders including FGR and PE.Impact StatementWhat is already known on this subject? It is known that angiopoietin-2 (Ang-2) has important role in placental angiogenesis and vascular remodelling. TM which is a receptor for Ang-2 plays a protective role in pregnancy by preventing the uteroplacental circulation from thrombosis.What do the results of this study add? The present study demonstrates that both midtrimester maternal plasma Ang-2/TM and amniotic fluid (AF) Ang-2 levels were significantly higher in PE and FGR group than uncomplicated group. Midtrimester AF TM levels were not significantly higher in PE group than the control group.What the implications are of these findings for clinical practice and/or further research? In the clinical practice, high levels of midtrimester Ang-2 and TM in plasma may be used for the prediction of FGR and PE. Although amniocentesis is not practical in the clinical use, the levels of these two markers in both AF and plasma compartments may contribute to explain the pathophysiology of FGR and PE.

Evaluation of maternal serum progesterone-induced blocking factor levels in pregnancies complicated with early- and late-onset preeclampsia.

The aim of present study was to evaluate maternal serum progesterone-induced blocking factor (PIBF) levels in pregnancies complicated with early-onset (EO-PE) and late-onset (LO-PE) preeclampsia. Patients with preeclampsia were divided in two groups according to preeclampsia onset and compared to healthy control group: EO-PE and LO-PE defined as being diagnosed before 340/7 and ≥340/7 weeks, respectively. Maternal age, nulliparity, BMI at blood sampling, smoking, history of caesarean section and ethnicity were statistically similar among the groups. Statistically significant differences were found between the eo-PE and lo-PE preeclampsia groups in terms of gestational age at delivery, mean birth-weight percentile and foetal growth restriction rates. The mean serum PIBF level was 528.6 ± 220 ng/mL in the eo-PE and 615.3 ± 269.1 ng/mL in the lo-PE preeclampsia and 782.3 ± 292.4 ng/mL in the control groups; the difference among groups was statistically significant. Our results indicated that decreased PIBF levels play an important immunologic role in preeclampsia onset. IMPACT STATEMENTWhat is already known on this subject? Maternal lymphocytes secrete PIBF that provides the immunological effects of progesterone during pregnancy by activating T-helper type 2 (Th2) cells and inhibiting any activated uterine natural killer (uNK) cells. The recent studies results have shown that there is disproportion in the Th1/Th2 rate in women with preeclampsia. This purports that Th1-mediated immunity is promoted through Th2-mediated immunity, which can be involved in the pathogenesis of preeclampsia.What do the results of this study add? In this study we found that PIBF levels in maternal serum were significantly lower in the EO-PE group than in LO-PE and control group. Our results indicated that decreased PIBF levels play an important immunologic role in preeclampsia onset.What are the implications of these findings for clinical practice and/or further research? We can speculate that first trimester maternal serum PIBF levels may be a useful biomarker for prediction of EO-PE. Using serum PIBF levels within the first trimester combined with Doppler values for the uterine artery, and some biochemical markers to predict onset and severity of preeclampsia appear to be a new screening method.

Evaluation of cardiac sphericity index among intrauterine growth restriction and normal fetuses.

Foetal growth restriction (FGR) describes the pregnancy complications of pathological reduced foetal growth, leading to significant perinatal mortality and morbidity, and subsequent long-term cardiovascular outcomes. This prospective case-control study was performed on pregnant women referred to the hospitals of Tehran University of Medical Sciences in 2017-2019. All pregnant women underwent ultrasound scan and doppler sonography. FGR was defined as a sonographic estimation of foetal weight below the tenth percentile for a given gestational age. Cardiac sphericity index, including basal-apical length (BAL), transverse length (TL), global sphericity index (GSI), umbilical artery pulsatility index (PI), middle cerebral artery (MCA) PI and cerebroplacental ratio (CPR) were assessed. Mean gestational age in FGR and control groups were 233.90 ± 22.00 days and 229.00 ± 25.02 days, respectively. Foetal size index and estimated foetal weight in FGR foetuses were significantly lower than the control group (p < .05). BAL, TL and GSI were significantly affected by FGR (p = .0001, p = .018 and p = .0001, respectively). Abnormal GSI, MCA PI, umbilical artery PI and CPR were significantly more prevalent among FGR foetuses (p = .017, p = .0001, p = .0001 and p = .0001, respectively). Cardiac sphericity index, as well as uterine PI, MCA PI and CPR, were the determinants of FGR in foetuses with normal Doppler and abnormal GSI.IMPACT STATEMENTWhat is already known on this subject? Foetal growth restriction (FGR) describes the foetus that does not grow to its expected biological potential in utero, and is a relatively common complication of pregnancy. FGR is accosted with negative birth outcomes and long-term cardiovascular outcomes. One of the indicators of FGR is cardiac sphericity.What do the results of this study add? The findings of this study revealed that the cardiac sphericity index as well as umbilical PI, MCA PI and CPR ratio change in FGR foetuses.What are the implications of these findings for clinical practice and/or further research? It is recommended that more studies be performed to follow FGR foetuses longitudinally and evaluate the long-term cardiac abnormalities in infancy and childhood and compare it between FGR foetuses and normal foetuses.

The relationship of foetal superior mesenteric artery blood flow and the time to first meconium passage in newborns with late-onset foetal growth restriction.

This study aimed to assess the relationship between the foetal superior mesenteric artery (SMA) Doppler and the time to first meconium passage (FMP) in foetuses with late-onset foetal growth restriction. This single-centre, prospective, observational, cohort study included 57 patients with late-onset FGR. The newborn infants were divided into two groups: preterm (36.8%) and term (63.2%). The time to FMP of the infants was compared to the foetal SMA parameters obtained within a week before delivery. The median time to FMP was similar between two groups (p = .31). The SMA pulsatility index (PI) was higher in the preterm group (p < .01). There was no correlation between foetal SMA PI or resistance index and time to FMP. In late-onset FGR infants, our study found no association between SMA Doppler measurements and time to FMP. However, a significant difference was detected in SMA PI between preterm and term infants. Impact StatementWhat is already known in this subject? Foetal growth restriction (FGR) can affect splanchnic circulation of the foetus and this alteration can be associated with some disorders including necrotising enterocolitis.What do the results of this study add? Superior mesenteric artery (SMA) Doppler indices are not associated with first meconium passage in neonates with late-onset foetal growth restriction. The pulsatility index of SMA is significantly higher in foetuses delivered before term.What are the implications of these findings for clinical practice and/or further research? Further research should be conducted to investigate the relationship between foetal SMA Doppler indices and neonatal gastrointestinal morbidities in foetuses with early onset FGR with Doppler anomalies. These studies can shed light from the prenatal to the postnatal period, allowing clinicians to predict potential problems and take precautions.

The utility of foetal splenic artery Doppler measurement in the diagnosis of late-onset foetal growth restriction.

We aimed to examine the contribution of splenic artery (SA) Doppler parameters in the detection of foetuses with late-onset foetal growth restriction (LO-FGR) and to evaluate its power in predicting adverse perinatal outcomes. Within the study's scope, 52 cases in the LO-FGR group and 92 cases in the control group were evaluated. The criteria determined in the Delphi procedure by an international consensus were used to define the LO-FGR. Middle cerebral artery (MCA) pulsatility index (PI) and SA PI were significantly lower in the LO-FGR group (p: .002, p<.001, respectively). Likewise, cerebroplacental ratio (CPR) was significantly lower in the LO-FGR group (p<.001). Decreased CPR and decreased SA PI were significantly and positively associated with an increased likelihood of exhibiting adverse obstetric outcome (p<.001, p: .012, respectively). The receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value for SA PI was 1.41 to predict LO-FGR with 70.7% sensitivity and 61.5% specificity (AUC = 0.684; 95% CI, 0.594-0.774).Impact StatementWhat is already known on this subject? The main clinical difficulty in late-onset foetal growth restriction (LO-FGR) is the detection of the disease.What do the results of this study add? The splenic artery (SA) pulsatility index (PI) may contribute to both diagnostic and the prediction of adverse perinatal outcomes in LO-FGR cases. Our results showed that the SA PI value, as well as cerebroplacental ratio (CPR), can be a useful parameter in predicting negative outcomes.What are the implications of these findings for clinical practice and/or further research? Various degrees of uteroplacental insufficiency in foetuses with LO-FGR may be associated with abnormalities in SA Doppler velocimetry. Splenic artery Doppler velocimetry can be used for the clinical management of LO-FGR.

Cerebroplacental doppler ratio and perinatal outcome in late-onset foetal growth restriction.

The purpose of this study was to determine whether gestational age-specific levels of the cerebroplacental ratio (CPR) as a third-trimester ultrasound marker has benefits in the prediction of perinatal morbidity and mortality on foetuses with late-onset foetal growth restriction (FGR). A retrospective study of singleton pregnancies diagnosed with late-onset FGR was performed. Of 407 pregnancies meeting our inclusion criteria, 313 had normal (Group 1) and 94 had abnormal CPR (Group 2). Both groups were similar in age, gestational age at diagnosis, body mass index and parity. There was a significant association between the presence of oligohydramnios and abnormal CPR. Mean gestational age at delivery and mean neonatal birth weight were significantly lower in Group 2. Neonatal intensive care unit admission, foetal distress, low 5-minute Apgar score <7, and low cord pH < 7.1 rates were significantly higher in Group 2. There was one neonatal death in both groups. Multivariable regression analysis demonstrated that, in the prediction of APO, there was a significant contribution from neonatal birth weight <10th percentile, CPR <5th percentile and oligohydramniosis. Our findings revealed that CPR value less than 5th centile can be used as a predictor of APO in late-onset FGR.IMPACT STATEMENTWhat is already known on this subject? Low cerebroplacetal ratio (CPR) is a marker of failure to reach the growth potential regardless of foetal weight.What do the results of this study add? The CPR can be used as an adequate predictor of adverse perinatal outcome in pregnancies with late-onset foetal growth restriction.What are the implications of these findings for clinical practice and/or further research? Routine calculation and report of CPR during basic ultrasound examination may help to identify foetuses with FR with a higher risk of adverse perinatal outcome. Future prospective studies on pregnancies with FGR with oligohydroamnios or normal amniotic fluid volume should focus on determining CPR threshold.

sFlt-1 to PlGF ratio cut-offs to predict adverse pregnancy outcomes in early-onset FGR and SGA: a prospective observational study.

This is a prospective, observational study, conducted in a tertiary referral hospital. We enrolled 175 singleton pregnancies with estimated foetal weight below the 10th centile between 20 + 0 and 31 + 6 weeks. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and fetoplacental circulation were assessed at the time of diagnosis. Receiver operating characteristic curves were used to assess the performance of sFlt-1/PlGF for predicting adverse perinatal outcomes (APO). The optimal cut-offs to predict each adverse outcome were calculated and the resulting areas under the curve (AUC) were compared to those calculated from the cut-off points of 38, 85 and 110. The need for delivery at <30 and <34 weeks and APO were the main outcome measures. The optimal cut-off points to predict APO, delivery <30 and <34 weeks were 24.9, 116.7 and 97.5, respectively. None of them proved to be superior to 38, 85 or 110 for predicting any adverse pregnancy outcome. Impact StatementWhat is already known on this subject? Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are biomarkers of placental dysfunction. High sFlt-1/PlGF values predict adverse perinatal outcomes in preeclampsia (PE).What do the results of this study add? No specific thresholds have been described to identify early-onset foetal growth restriction (FGR) and small for gestational age (SGA) foetuses at higher risk of adverse outcomes. This study describes these specific cut-offs and compares their predictive capacity to those described for PE.What are the implications of these findings for clinical practice and/or further research? The sFlt-1/PlGF cut-off points of 38, 85 and 110 might be useful for ruling out the occurrence of APO and the need for elective delivery at <30 and at <34 weeks from the moment of diagnosis in early-onset FGR and SGA. These cut-offs could aid Doppler studies in the distinction between FGR and SGA.

[Impact of asymptomatic maternal SARS-CoV-2 infection on foetal growth]. / Impacto de la infección materna asintomática por SARS-CoV-2 sobre el crecimiento fetal.

Introduction: The impact of asymptomatic infection by SARs-CoV-2 on foetal growth has not been described. The purpose of our study is to determine whether there is an increased risk of foetal growth restriction in pregnancies in which asymptomatic or mild infection by SARS-CoV-2 has been detected. Material and methods: Retrospective case-control study with a subset of pregnant women with a small for gestational age foetus. Groups were established according to birth weight percentile. Previous SARS-CoV-2 infection was defined by positive antibodies obtained on admission to hospital for delivery. Results: No statistically significant differences between controls and cases were recorded in terms of positive IgG antibodies (11.5 vs. 8.8%). There were no premature births or significant differences in the date or type of delivery. Conclusions: Asymptomatic infection by SARs-CoV-2 during pregnancy does not seem to affect foetal growth.

Children born before 32 weeks of gestation displayed impaired reading fluency, comprehension and spelling skills at 9 years of age.

AIM: Our aim was to study whether prematurity, associated with prenatal and neonatal risk factors, affects specific literacy skills among school children born at a very low gestational age (VLGA) of <32 weeks. METHODS: The study group comprised 76 prospectively followed VLGA children born between November 1998 and November 2002 at Oulu University Hospital, Finland, and 51 term controls. The median gestational age of the VLGA children was 29.0 (24.1-31.9) weeks. All children were examined at a median age of 8.9 (8.0-9.9) years in Oulu between November 2007 and November 2011. Reading fluency, comprehension and spelling skills were evaluated using standardised tests for Finnish-speaking children. RESULTS: Very low gestational age children had significantly poorer test results in reading comprehension (median 6.9 vs 8.3, P = .014) and spelling (median 35.7 vs 38.0, P = .013) than term children. Furthermore, VLGA children more often performed below the 10th percentile normal values in spelling (P = .012) compared with term controls. Foetal growth restriction was associated with lower scoring in reading fluency (P = .023) and spelling (P = .004) among VLGA children. CONCLUSION: Very low gestational age school children performed poorer in reading comprehension and spelling than term children. In addition, poor foetal growth in VLGA children was associated with literacy problems.

Influence of maternal region of birth on neonatal outcomes of babies born small.

AIM: To compare neonatal outcomes of small for gestational age (SGA) infants born to South Asian (SA)-born women and Australian/New Zealand (ANZ)-born women. METHODS: Retrospective cohort study at a hospital network in Australia. Maternal and neonatal data were collected for infants born SGA between 2013 and 2017 to SA- or ANZ-born women. Rates of perinatal mortality and neonatal morbidities were analysed between groups. RESULTS: A total of 1018 SA and 959 ANZ SGA infants were included. SA SGA babies were older (median [IQR] 39 [38-40] weeks) and heavier (2590 [2310-2780] grams) compared to ANZ SGA babies (38 [37-40] weeks and 2480 [2059-2740] grams; P < .001 for both). After adjustment for differences in demographics, SA SGA babies were 1.5 times more likely to develop hypothermia (CI: 1.16-1.88, P = .001), but 60% less likely to be born with a major congenital malformation (CI: 0.24-0.67, P = .001) and 36% less likely to need gavage feeding (CI: 0.43-0.93, P = .02) compared to ANZ SGA babies. CONCLUSION: Small for gestational age babies of SA-born women have different neonatal outcomes as compared to those born to ANZ-born women. Further research into influence of maternal region of birth on placental function, organogenesis and body composition of SGA babies is warranted.

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.