Early-onset Fetal Growth Restriction Research Articles

The genetics and clinical outcomes in 151 cases of fetal growth restriction: A Chinese single-center study

ObjectiveTo determine the detection rate of chromosomal abnormalities and pregnancy outcomes in fetuses with intrauterine growth restriction.Study designA total of 151 fetal samples with intrauterine growth restriction were were divided into the isolated fetal growth restriction (FGR) group, FGR group with structural malformation, and FGR group with non-structural malformation, according to ultrasound abnormalities. The enrolled patients were divided into an early onset FGR group (<32 weeks) and a late-onset FGR group (≥32 weeks). Chromosomal karyotype and microarray analyses were performed and pregnancy outcomes were monitored.ResultsThe karyotypes of 122 patients were analyzed. Four patients exhibited abnormal chromosome numbers or structures. Variations in copy number were detected in 151 cases; 19 cases were found to have chromosomal abnormalities, with a positivity rate of 12.6 %. There was one trisomy in 18 cases, one trisomy in 21 cases, eight pathogenic copy number variations (CNVs), and nine CNVs of unknown clinical significance. The detection rate of FGR combined with structural malformation was significantly higher than that of isolated FGR group. The detection rate of FGR with structural malformations was significantly higher than that with non-structural malformations. The positive detection rate in the FGR group was similar to that in the FGR group with non-structural malformations, with no statistical significance. Chromosomal abnormalities were detected in 17 patients with early onset FGR, with a positivity rate of 13.8 %. Two cases of chromosomal abnormalities were detected in the late-onset FGR group, with a positive rate of 7.1 %, with no statistical significance. A total of 151 fetuses with FGR were followed up for pregnancy outcomes, resulting in 36 cases of pregnancy termination and 13 cases of loss to follow-up. Among the 102 delivered fetuses, six exhibited delayed growth and development, one presented with hypospadias, and another failed the hearing screening. The remaining 94 fetuses demonstrated normal growth and development.ConclusionsThis study confirms the value of CNV detection in fetuses and dynamic ultrasound monitoring for fetuses with intrauterine growth restriction.

Etiologic evaluation and pregnancy outcomes of fetal growth restriction (FGR) associated with structural malformations

This study aimed to evaluate the etiology and pregnancy outcomes of fetuses underwent invasive prenatal diagnosis for fetal growth restriction (FGR) accompanied by structural malformations. Data from 130 pregnancies referred for prenatal diagnosis for FGR accompanied by structural malformations were obtained between July 2011 and July 2023. Traditional karyotyping was conducted for all the subjects. A total of 37 (28.5%) cases of chromosomal abnormalities were detected by karyotyping, including 30 cases of numerical anomalies and seven cases of unbalanced structural anomalies. Trisomy 18 was the most common abnormalities, accounting for 51.4%, significantly higher than any other chromosomal abnormality. The cohort was predominantly comprised of early-onset FGR (88.5%) compared to late-onset FGR (11.5%). The incidences of chromosomal abnormalities in this two groups were 29.6% (34/115) and 20.0% (3/15), respectively (p > 0.05). The majority (74.6%, 97/130) of the cohort were affected by a single system malformation, with chromosomal abnormalities found in 19.6% (19/97) of cases. In pregnancies of structural malformations involving two and multiple systems, the frequencies were 56.5% (13/23), and 50.0% (5/10), respectively. Single nucleotide polymorphism array (SNP array) was performed in parallel for 65 cases, revealing additional 7.7% cases of copy number variants (CNVs) compared to karyotyping. Polymerase chain reaction (PCR) was used for detection of cytomegalovirus (CMV) DNA in 92 cases. All fetuses with FGR associated with two or more system malformations were either terminated or stillborn, irrespective of chromosomal aberrations. Conversely, 71.8% of pregnancies with a single-system malformation and normal genetic testing results resulted in live births. Furthermore, two (2.2%) cases tested positive for CMV DNA, leading to one termination and one case of serious developmental disorder after birth. Our study suggests that structural malformations associated with FGR are more likely to affect a single organ system. When multiple systems are involved, the incidence of chromosomal abnormalities and termination rates are notably high. We advocate for the use of CMA and CMV DNA examinations in FGR cases undergo invasive prenatal diagnosis, as these tests can provide valuable insights for etiological exploration and pregnancy management guidance.

The role of the ratio of first trimester CRL (crown rump length) measurement to NT (nuchal translucency) measurements in predicting early-onset fetal growth restriction (FGR)

Objective: Our aim is to evaluate the role of the ratio of first-trimester CRL (crown rump length) measurement to NT (nuchal translucency) measurements in predicting early-onset fetal growth restriction (FGR) and to contribute to the existing literature.&#x0D; Methods: In the present case-control study, fetuses with early-onset FGR were compared to a frequency matched low risk control group. This study was conducted in the perinatology clinic of Ankara Bilkent City Hospital between 2020 and 2023. Maternal age, gravidity, parity, crown-rump length (CRL), and nuchal translucency (NT) measurements were compared between pregnant women with early onset FGR (n=39) and pregnant women without FGR (n=50).&#x0D; Results: The mean age of pregnant women with FGR who participated in the study was 27.1±0.8, and the mean age of pregnant women without FGR was 26.3±0.6, and no statistically significant difference was found between the two groups (p=0.4)). Mean CRL was 54.98±1.08 mm in the group with FGR and 56.99±1.11 mm in the group without FGR; there was no significant difference between the two groups (p=0.2). The NT value was 1.11 ± 0.04 mm in the FGR group and 1.13 ± 0.02 mm in the without FGR group, there was no significant difference between the two groups (p=0.73). The mean CRL/NT ratio was 52.00±2.33 in the group with early onset FGR and 51.46±1.48 in the group without FGR and there was no statistically significant difference between the two groups (p=0.83).&#x0D; When the early developing FGR group is evaluated within itself, the mean age at diagnosis was 31.7±0.3 weeks. EFW mean percentile at diagnosis was 4.5±0.6 and ac percentile was 2.9±0.4. The mean umbilical artery systole/diastole ratio (UA-SD) was 2.9±0.16 and the mean umbilical artery pulsatility index (UA-PI) was 1.02±0.05.&#x0D; Conclusion: Crown-rump length to nuchal translucency ratio is not clinically useful to predict early-onset FGR.

Prenatal Features of MIRAGE Syndrome-Case Report and Review of the Literature.

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the "de novo" mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care.

Placental differences between severe fetal growth restriction and hypertensive disorders of pregnancy requiring early preterm delivery: morphometric analysis of the villous tree supported by artificial intelligence

The "great obstetrical syndromes" of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether one or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways. To determine how quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent/reversed umbilical artery Doppler indices, hypertensive disorders of pregnancy, and the two conditions combined among subjects with disease severity warranting early preterm delivery. We hypothesize that trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulate that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction, with no additional effect when hypertension is concomitantly present. In this retrospective cohort study, paraffin-embedded placental tissue was obtained from four groups: [1] Severe fetal growth restriction with absent/reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, [2] Severe fetal growth restriction with absent/reversed umbilical artery Doppler indices and no hypertension,[3] Gestational age-matched, appropriately grown pregnancies with hypertensive disease, and [4] Gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed followed by artificial intelligence-driven morphometric analyses. Number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled with linear regression. Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi, 95% CI: [-467, -98], p<0.01), smaller stem villous area (-4.3 mm2, 95% CI: [-7.3, -1.2], p<0.01), and fewer stem villous vessels (-4967 stem villous vessels, 95% CI [-8501, -1433], p<0.01), with no difference in total vascular area. In contrast, placental abnormalities in severe growth restriction were limited to terminal villi, with global decreases in number of villi (-873 terminal villi, 95% CI: [-1501, -246], p<0.01), villous area (-1.5 mm2, 95% CI: [-2.7, -0.4], p<0.01), number of blood vessels (-5165 terminal villous vessels, 95% CI: [-8201, -2128], p<0.01), and vascular area (-0.6 mm2, 95% CI: [-1.1, -0.1], p=0.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state. Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent/reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions with the combination of growth restriction and hypertension, suggesting that distinct pathophysiologic pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to result in more severe pathologic consequences. Delineating mechanisms underlying the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.

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

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

Rate of deterioration of umbilical artery Doppler indices in fetuses with severe early-onset fetal growth restriction

ObjectiveTo examine risk factors for the development of absent or reversed end-diastolic velocity (A/REDV) and the time intervals of deterioration from normal UA EDV by S/D, PI or RI to decreased and A/REDV in fetuses with early-onset severe FGR. Study DesignRetrospective cohort study performed from 2005 to 2020. All singleton pregnancies with severe (estimated fetal weight [EFW] or abdominal circumference [AC] below the 3rd percentile) and early-onset (diagnosed between 20 0/7 to 31 6/7 weeks of gestation) were included. Fetal genetic or structural anomalies, suspected congenital infections, A/REDV at diagnosis, poor pregnancy dating and absence of follow-up ultrasounds were excluded. EFW, AC and Doppler indices were reviewed longitudinally from diagnosis to delivery. To examine risk factors for A/REDV, we performed backward stepwise logistic regression and calculated odds ratio with 95% confidence interval (CI). Kaplan-Meier curves were compared using log-rank test. ResultsA total of 985 patients met the inclusion criteria and 79 (8%) progressed to A/REDV. Factors associated with development of A/REDV included gestational age at diagnosis (AOR 4.88 [2.55 – 9.37, 95% CI] at 20 0/7 to 23 6/7 weeks and AOR 1.56 [0.86-2.82, 95%CI] at 24 0/7 to 27 6/7 weeks compared to 28 0/7 to 31 6/7 weeks) and presence of chronic hypertension (CHTN) with AOR 2.37 (1.33 – 4.23, 95% CI). Rates of progression from diagnosis of FGR with normal UA Doppler to A/REDV were significant after 4 weeks from diagnosis (5.84% [4.50 – 7.57, 95% CI]). Regarding the Doppler indices, the progression from normal values to abnormal indices was similar in 1 and 2 weeks however the progression from normal to abnormal S/D ratio compared to PI or RI were higher at 4 and 6 weeks. Deterioration from abnormal indices to A/REDV was shorter with abnormal RI and PI when compared to S/D ratio at 2, 4 and 6 weeks after diagnosis and at 6 weeks, respectively. ConclusionEarlier gestational age at diagnosis and CHTN are considered risk factors for Doppler deterioration and development of A/REDV in the UA. With normal Doppler indices, significant deterioration and progression to A/REDV is unlikely until 4 weeks after diagnosis. Abnormal S/D ratio seems to be appear first. However, abnormal PI or RI was associated with A/REDV.

Clinical significance of three-dimensional power Doppler combined with two-dimensional Doppler ultrasonography for evaluating fetal growth restriction

Objectives To assess the predictive accuracy of three-dimensional (3D) power Doppler combined with two-dimensional (2D) Doppler ultrasonography in detecting fetal growth restriction (FGR). Methods The study was conducted on singleton pregnancies presenting for growth ultrasound examinations between 20 and 40 weeks of gestation. 63 patients with FGR were enrolled and matched 1:1.8 for gestational age with normal fetuses. Both groups were further divided into subgroups, with 32 weeks as the threshold—early-onset and late-onset FGR groups, and corresponding control groups. Conventional 2D Doppler parameters and standardized 3D power Doppler measurements of the placenta, including vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were obtained for each patient. Results (1) The average gestational weeks of delivery and birth weight of newborns in early-onset and late-onset FGR case groups were lower than those in control groups, while the incidence of placenta previa and adverse pregnancy outcomes were higher than those in control groups. (2) The biparietal diameter, head circumference, abdominal circumference, femur length, estimated fetal weight, middle cerebral artery systolic/diastolic velocity ratio (S/D), pulsatility index (PI), resistance index (RI), and placental blood perfusion indices of vascular index (VI), flow index (FI), vascular flow index (VFI), and cerebro-placental ratio (CPR) of the early-onset and late-onset FGR case groups were all lower than those of the control group. Moreover, the S/D, PI, and RI of the umbilical and uterine arteries were higher than those of the corresponding control group. (3) For early-onset FGR, the area under the curve (AUC) of the umbilical artery PI was the largest (0.861), exhibiting the highest predictive value. When combined with the placental blood perfusion index, the AUC was 0.789. For late-onset FGR, the AUC of the CPR was 0.861. After integrating the placental blood perfusion index, the AUC increased to 0.877. The positive likelihood ratio (PLR) of combined 2D Doppler indexes (21.938) and negative likelihood ratio (NLR) of VFI (0.565) were the highest in the early-onset FGR group. The PLR of combined 3D Doppler indexes (8.536) and NLR of VFI (0.557) were the highest in the late-onset FGR group. Conclusions The combination of 3D Doppler indices with 2D Doppler ultrasonography demonstrated superior predictive value in diagnosing late-onset FGR compared to other conventional indicators. The 3D Dower index, VFI, has a good true-negative predictive value for both early- and late-onset FGR.

1068 Pregnancy Outcomes in Severe Early-Onset Fetal Growth Restriction: Results from the Multicenter PERIMETER Study

1068 Pregnancy Outcomes in Severe Early-Onset Fetal Growth Restriction: Results from the Multicenter PERIMETER Study

Phenotype of early-onset fetal growth restriction in sheep.

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

Systemic Oxidative Stress in Severe Early-Onset Fetal Growth Restriction Associates with Concomitant Pre-Eclampsia, Not with Severity of Fetal Growth Restriction.

Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = -0.281 p = 0.004, pre-eclampsia; ρ = -0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = -0.348 p = 0.001) and diastolic blood pressure (ρ = -0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = -0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.

Reduced in utero substrate supply decreases mitochondrial abundance and alters the expression of metabolic signalling molecules in the fetal sheep heart.

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life.

Practice variation in timing of antenatal corticosteroid administration in early-onset fetal growth restriction: Asecondary analysis of the Dutch STRIDER study.

In early-onset fetal growth restriction the fetus fails to thrive in utero due to unmet fetal metabolic demands. This condition is linked to perinatal mortality and severe neonatal morbidity. Maternal administration of corticosteroids in high-risk pregnancies for preterm birth at a gestational age between 24 and 34 weeks has been shown to reduce perinatal mortality and morbidity. Practice variation exists in the timing of the administration of corticosteroids based on umbilical artery monitoring findings in early-onset fetal growth restriction. The aim of this study was to examine differences in neonatal outcomes when comparing different corticosteroid timing strategies. This was a post-hoc analysis of the Dutch STRIDER trial. We examined neonatal outcomes when comparing institutional strategies of early (umbilical artery pulsatility index >95th centile) and late (umbilical artery shows absent or reversed end-diastolic flow) administration of corticosteroids. The primary outcomes were neonatal mortality and a composite of neonatal mortality and neonatal morbidity, defined as bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis or retinopathy of prematurity. We also analyzed predictors for adverse neonatal outcomes, including gestational age at delivery, birthweight, maternal hypertensive disorders, and time interval between corticosteroids and birth. A total of 120 patients matched our inclusion criteria. In 69 (57.5%) the early strategy was applied and in 51 (42.5%) patients the late strategy. Median gestational age at delivery was 28 4/7 (± 3, 3/7) weeks. Median birthweight was 708 (± 304) g. Composite primary outcome was found in 57 (47.5%) neonates. No significant differences were observed in the primary outcome between the two strategies (neonatal mortality adjusted odds ratio [OR] 1.22, 95% CI 0.44-3.38; composite primary outcome adjusted OR 1.05, 95% CI 0.42-2.64). Only gestational age at delivery was a significant predictor for improved neonatal outcome (adjusted OR 0.91, 95% CI 0.86-0.96). No significant differences in neonatal outcomes were observed when comparing early and late strategy of antenatal corticosteroid administration on neonatal outcomes in pregnancies complicated by early-onset fetal growth restriction. We found no apparent risk contribution of interval between corticosteroid administration and delivery in multivariate analysis. Gestational age at delivery was found to be an important predictor of neonatal outcome.

Impact of early-onset fetal growth restriction on the neurodevelopmental outcome of very preterm infants at 24 months: a retrospective cohort study

BackgroundThe association between fetal growth restriction (FGR) and childhood neurodevelopmental delay is unclear and the evidence available to the present date shows conflicting results. Our aim was to analyse the impact of early-onset FGR on the neurodevelopmental outcome at 24 months of corrected age in very preterm infants.MethodsRetrospective cohort study of very preterm infants (≤ 32 weeks’ gestation) admitted to a neonatal intensive care unit between 1 January 2013–31 December 2019. The control group comprised appropriate for gestational age (AGA) newborns. Griffiths III Mental Development Scale was performed at 24 months of corrected age.Results132 infants were included: 44 FGR and 88 AGA. Mean Global Development Quotient (GDQ) was lower for FGR infants (p = 0.004) even after adjusting for maternal and perinatal factors (βadjusted -16.703; p = 0.009). The average scores for the neurodevelopmental domains were highest for personal-social-emotional skills (107.02 ± 16.34), followed by eye/hand coordination (105.61 ± 14.20) and foundation of learning skills (102.23 ± 13.74) and were lowest for gross motor (97.90 ± 11.88) and language/communication skills (96.39 ± 18.88). FGR had a significant negative impact on all domains except for gross motor skills. After adjustment, FGR continued to have a significant adverse impact on language/communication (βadjusted -21.924; p = 0.013), eye/hand coordination (βadjusted -15.446; p = 0.015) and foundation of learning skills (βadjusted -15.211; p = 0.013).ConclusionsIn very preterm infants, FGR was associated with a significantly increased risk of poor neurodevelopmental outcome at 24 months of corrected age compared to age-matched AGA infants.

Effect of low-molecular-weight heparin on placenta-mediated fetal growth restriction in a tertiary referral hospital: A 7-year retrospective cohort study.

To investigate the effect of low-molecular-weight heparin (LMWH) on placenta-mediated fetal growth restriction (FGR). A cohort of 570 pregnant women diagnosed with placenta-mediated FGR were enrolled from January 1, 2015 through to December 31, 2021. A birth database, including demographic data, antenatal complications, and detailed delivery and newborn data, was created to collect variables from the Hospital Information System (HIS) Database. The unique personal registration number, assigned to each patient on first registration with HIS in the West China Second University Hospital, was used to link these patients. LMWH use was defined as at least 1-week prescription from diagnosis of placenta-mediated FGR. Pregnant women received LMWH (Enoxaparin 4000 IU/day) by self-administered subcutaneous injection only when they agreed and signed informed consent. Primary outcome was intrauterine fetal death after 20 weeks of pregnancy. Secondary outcomes included preterm birth (PB), Apgar score less than 7 at 1 min, admission to neonatal intensive care unit (NICU), and birth weight. Logistic regression analysis was conducted to compute adjusted odds ratio (aOR) with 95% confidence intervals (CI) for outcomes. After controlling for confounders, LMWH use was associated with a decreased risk of intrauterine fetal death (aOR 2.49, 95% CI 1.35-4.57, P = 0.003), PB before 37 weeks of pregnancy (aOR 3.35, 95% CI 2.14-5.23, P < 0.001), PB before 34 weeks of pregnancy (aOR 2.25, 95% CI 1.36-3.74, P = 0.002), Apgar score less than 7 at 1 min (aOR 2.25, 95% CI 1.36-3.74, P = 0.002), NICU admission (aOR 2.29, 95% CI 1.48-3.55, P < 0.001). Using LMWH increased the mean birth weight in PB before 32 weeks of pregnancy (mean ± standard deviation [SD] 1126.4 ± 520.0 g, P = 0.020), PB before 37 weeks of pregnancy (mean ± SD 1563.9 ± 502.7 g, P = 0.019), early-onset FGR (mean ± SD 2125.2 ± 665.7 g, P < 0.001), late-onset FGR (mean ± SD 2343.4 ± 507.9, P < 0.001), and non-severe FGR (mean ± SD 2231.1 ± 607.2 g, P < 0.001). Use of LMWH can significantly improve the fetal and neonatal outcomes among pregnant women with placenta-mediated FGR, particularly reducing the risk of intrauterine fetal death.

Scaling the EVERREST of severe, early-onset fetal growth restriction.

Severe, early-onset fetal growth restriction is a leading cause of medically indicated preterm birth and substantially increases the risk for perinatal death or disability. No treatments exist to improve fetal growth or safely prolong pregnancy. Furthermore, wide-ranging phenotypes limit the accurate prediction of pregnancy outcome. In this issue of the JCI, Spencer and colleagues combine a discovery-science approach with ultrasound parameters to identify the most discriminative models for predicting either the primary outcome of fetal or neonatal death, or a secondary outcome of death or delivery at 28 weeks of gestation or earlier. Their findings can better individualize patient counseling but, just as compellingly, provide the capacity to identify those pregnancies that are at such considerable risk as to justify enrollment in paradigm-shifting interventional trials that are in the pipeline.

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

Early Fetal Growth Restriction with or Without Hypertensive Disorders: a Clinical Overview.

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR.

PO1_11. Optimal timing of antenatal corticosteroid administration in pregnancies complicated by early-onset fetal growth restriction: The opticore study protocol

PO1_11. Optimal timing of antenatal corticosteroid administration in pregnancies complicated by early-onset fetal growth restriction: The opticore study protocol

The medullary serotonergic centres involved in cardiorespiratory control are disrupted by fetal growth restriction.

Fetal growth restriction (FGR) is associated with cardiovascular and respiratory complications after birth and beyond. Despite research showing a range of neurological changes following FGR, little is known about how FGR affects the brainstem cardiorespiratory control centres. The primary neurons that release serotonin reside in the brainstem cardiorespiratory control centres and may be affected by FGR. At two time points in the last trimester of sheep brain development, 110 and 127days of gestation (0.74 and 0.86 of gestation), we assessed histopathological alterations in the brainstem cardiorespiratory control centres of the pons and medulla in early-onset FGR versus control fetal sheep. The FGR cohort were hypoxaemic and asymmetrically growth restricted. Compared to the controls, the brainstem of FGR fetuses exhibited signs of neuropathology, including elevated cell death and reduced cell proliferation, grey and white matter deficits, and evidence of oxidative stress and neuroinflammation. FGR brainstem pathology was predominantly observed in the medullary raphé nuclei, hypoglossal nucleus, nucleus ambiguous, solitary tract and nucleus of the solitary tract. The FGR groups showed imbalanced brainstem serotonin and serotonin 1A receptor abundance in the medullary raphé nuclei, despite evidence of increased serotonin staining within vascular regions of placentomes collected from FGR fetuses. Our findings demonstrate both early and adaptive brainstem neuropathology in response to placental insufficiency. KEY POINTS: Early-onset fetal growth restriction (FGR) was induced in fetal sheep, resulting in chronic fetal hypoxaemia. Growth-restricted fetuses exhibit persistent neuropathology in brainstem nuclei, characterised by disrupted cell proliferation and reduced neuronal cell number within critical centres responsible for the regulation of cardiovascular and respiratory functions. Elevated brainstem inflammation and oxidative stress suggest potential mechanisms contributing to the observed neuropathological changes. Both placental and brainstem levels of 5-HT were found to be impaired following FGR.