Preterm Fetal Growth Restriction Research Articles

Impact of Endocrine-Disrupting Chemicals, Climate, and Air Pollution on Pregnancy Outcomes: A Scoping Review.

Environmental pollutants, including endocrine-disrupting chemicals (EDCs), air pollution, and climate change, are increasingly recognized for their potential impact on pregnancy outcomes. EDCs, found in pesticides, industrial chemicals, and personal care products, are associated with preterm birth and fetal growth restriction, primarily through hormonal interference. Air pollution, notably PM2.5, NO2, and O3, has been linked to increased rates of preterm birth, low birth weight, and stillbirth. Climate factors, such as extreme heat, elevate risks of pregnancy loss and preterm birth, with significant impacts on vulnerable populations across diverse socioeconomic and geographic regions. These exposures contribute to adverse pregnancy outcomes through mechanisms involving oxidative stress, inflammation, and endocrine disruption. The interplay among these environmental factors underscores the need for integrated, longitudinal studies to understand their combined effects on pregnancy outcomes better. Future research should focus on region-specific impacts, cumulative exposure, and policy-driven interventions to mitigate these environmental risks, especially in vulnerable populations disproportionately affected by these hazards. This scoping review synthesizes recent findings from 2019 to 2024 to highlight these associations and identify research gaps.

Metabolomic biomarkers in amniotic fluid for early diagnosis of preterm birth and fetal growth restriction.

Preterm birth, affecting about 10% of pregnancies, significantly contributes to perinatal morbidity and mortality. Recent research indicates that metabolomics could enhance pregnancy outcomes and reduce costs by identifying biomarkers related to common pregnancy complications. Our team focused on analyzing amniotic fluid collected during the second trimester to identify potential biomarkers for preterm birth using 1H-NMR metabolomic analysis. We compared amniotic fluid samples from women who delivered prematurely with those who delivered at term. Multivariate principal component analysis revealed dimethylglycine, glucose, myo-inositol, and succinic acid as potential biomarkers for preterm birth prognosis and early diagnosis. Further analysis demonstrated distinct regulation patterns of these metabolites in relation to fetal growth centiles. For instance, dimethylglycine and glucose were upregulated in fetuses above the 20th centile, while citrate and succinate were upregulated in those below it. With Area Under the Curve (AUROC) values over 0.75 and p-values less than 0.05, these metabolites show promise as reliable biomarkers for predicting fetal growth restriction. This approach could significantly impact maternal-fetal medicine by facilitating early diagnosis and personalized interventions. Future research should focus on validating these findings in larger populations and exploring the underlying mechanisms of metabolite regulation.

Association between Gestational Weight Gain and Pregnancy Outcomes in Various Body Mass Index Groups: A Retrospective Observational Study

Abstract Introduction: Body mass index (BMI) has been known to be an important determinant of pregnancy morbidities. However, multiple studies show that the effects are equally dependent on the gestational weight gain (GWG). There is a lack of data in the Indian population, especially using the Asia–Pacific guidelines of BMI. This study is meant to identify the degree of association between the GWG in different BMIs and the development of pregnancy morbidities. Materials and Methods: This was a retrospective study, in which case records of women who delivered in our hospitals during 1 year were analyzed. Pregnancy outcomes, such as growth restriction, preterm deliveries, development of hypertensive disorders, gestational diabetes, inductions, and cesareans, were analyzed in three classes of GWG inadequate, adequate, and excess GWG (as per institue of medicine guidelines). The Chi-square test was done to see the difference in the pregnancy outcomes. Results: Of the 1396 women enrolled, women with inadequate GWG had higher preterm deliveries (13.8% vs. 4.4%, P < 0.001) and fetal growth restriction (8.8% vs. 3.9%, P = 0.003) with higher odds in underweight women with inadequate GWG (odds ratio [OR] of 2.6 and 1.75, respectively). Excess GWG had a significantly higher induction (34.9% vs. 29%, P > 0.05) and cesarean delivery rate (34.3% vs. 21.6%, P = 0.003) with higher odds seen in obese women with excess GWG (OR of 2.6 and 1.75, respectively). Conclusion: All women having out-of-range BMI should be identified during the first antenatal contact. Inadequate GWG in underweight women and excess GWG in obese women should be strictly monitored and targeted to prevent a wide spectrum of maternal morbidities.

Vascular responsiveness to low-dose dexamethasone in extremely premature infants: negative influence of fetal growth restriction.

Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-/postintervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm fetal growth restriction (FGR) infants compared with appropriate for gestational age (AGA) infants. Echocardiography was performed within 24 h before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birth weight, 25.2 ± 1.1 wk and 497 ± 92 g, respectively) were compared with 22 AGA infants (gestation and birth weight, 24.5 ± 0.8 and 663 ± 100 g, respectively). Baseline respiratory severity score (mean airway pressure × fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR, 10 [6, 13] vs. AGA, 8 ± 2.8, P = 0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR, 0.19 ± 0.03 vs. AGA, 0.2 ± 0.03, P = 0.16) and right ventricular output (FGR, 171 ± 20 vs. 174 ± 17 mL/kg/min, P = 0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in the respiratory severity score was significantly greater in AGA infants (median [interquartile range] FGR, 10 [6, 13] to 9 [2.6, 13.5], P = 0.009 vs. AGA, 8 ± 2.8 to 3 ± 1, P < 0.0001). Improvement in measures of pulmonary vascular resistance (ratio of time to peak velocity to right ventricular ejection time) was greater in AGA infants (FGR, 0.19 ± 0.03 to 0.2 ± 0.03, P = 0.13 vs. AGA 0.2 ± 0.03 to 0.25 ± 0.03, P < 0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171 ± 20 to 190 ± 21, P = 0.014 vs. 174 ± 17 to 203 ± 22, P < 0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in utero maladaptive state.NEW & NOTEWORTHY Dexamethasone (DEX) is frequently used in preterm infants dependent on ventilator support. Differences in vascular structure and function that may have developed prenatally arising from the chronic intrauterine hypoxemia in FGR infants may adversely affect responsiveness. The clinical efficacy of DEX was significantly less in FGR (birth weight < 10th centile) infants, compared with appropriate for gestational age (AGA) infants. Echocardiography showed significantly less improvement in pulmonary vascular resistance in FGR, compared with AGA infants.

Abstract P207: Regulation of Fetal-Placental ACE and ACE2 in COVID-19 Exposed Pregnancies Compared to Hypertensive and Healthy Pregnancies

Introduction: Higher risks of preterm birth and fetal growth restriction are observed in COVID-19 pregnancies. The infection mechanism, linked to a potential depletion of the cardioprotective protein ACE2, which serves as a receptor for SARS-CoV-2, could pose additional risks for mothers and fetuses. An ACE2/ACE imbalance, favoring ACE, has been seen in hypertensive (HT) pregnancies and is linked to poor outcomes, including pre-eclampsia. This study aims to assess whether similar changes in ACE and ACE2 regulation in placentas and umbilical cord blood occur in COVID-19 compared to HT and healthy (Ctrl) pregnancies, and whether this imbalance is associated with impaired vascular structure. Methods: A retrospective cohort study recruited 77 pregnancies (25 COVID-19, 16 HT, 36 Ctrl) at Montreal Hospital Sacré-Coeur. Placental infarction was assessed in histological sections, umbilical cord fibrosis by Masson's trichrome staining, and placental ACE2 content by immunohistochemistry. ACE and ACE2 activity were measured by fluorometric assay in umbilical cord plasma. Data are presented as mean 95% CI. Linear regression was used for correlations, Kruskal-Wallis and Mann-Whitney tests for group comparisons. Results: Maternal age, gestational age, and the proportion of male/female fetuses were similar between groups. Ctrl group had lower rates of C-section delivery, obesity, and gestational diabetes compared to COVID-19 and HT pregnancies. Although ACE2 content in placentas was reduced in HT pregnancies, the COVID-19 group had significantly higher content compared to HT and Ctrl pregnancies (23.4 CI=20.4-26.4 vs. 15.5 CI=9.7-21.3 and 17.6 CI=15.1-20.1, respectively, p&lt;0.01). The ACE2/ACE activity ratio in cord blood was significantly reduced in COVID-19 and HT groups compared to Ctrl (3.1 CI=2.4-3.6, 2.5 CI=1.7-3.1, and 4.1 CI=3.5-4.8, p&lt;0.01), indicating an imbalance favoring ACE activity in HT and COVID-19 groups. The ACE2/ACE ratio negatively correlated with umbilical cord fibrosis (slope=-3.1 CI= -6.1 to -0.1, p=0.04) and was significantly lower in placentas with tissue infarction (2.5 CI=1.2-3.8 vs. 4.6 CI=3.8-5.3, p&lt;0.01). Conclusion: HT pregnancies have reduced ACE2 content and an ACE2/ACE activity imbalance in cord blood. COVID-19 pregnancies show a similar imbalance in cord blood but significantly higher ACE2 content in the placenta. This imbalance is associated with structural changes in fetal-placental vessels, suggesting a link to poor pregnancy outcomes.

Trophoblast Side-Population Markers are Dysregulated in Preeclampsia and Fetal Growth Restriction

Dysregulated progenitor cell populations may contribute to poor placental development and placental insufficiency pathogenesis. Side-population cells possess progenitor properties. Recent human trophoblast side-population isolation identified enrichment of 8 specific genes (CXCL8, ELL2, GATA6, HK2, HLA-DPB1, INTS6, SERPINE3 and UPP1) (Gamage et al. 2020, Stem Cell Rev Rep). We characterised these trophoblast side-population markers in human placenta and in placental insufficiency disorders: preeclampsia and fetal growth restriction (FGR). Trophoblast side-population markers localised to mononuclear trophoblasts lining the placental villous basement membrane in preterm control, preeclamptic and FGR placental sections (n = 3, panel of 3 markers/serial section). Analysis of single-cell transcriptomics of an organoid human trophoblast stem cell (hTSC) to extravillous trophoblast (EVT) differentiation model (Shannon et al. 2022, Development) identified that all side-population genes were enriched in mononuclear trophoblast and trophoblasts committed to differentiation under hTSC culture conditions. In vitro validation via 96 h time course hTSC differentiation to EVTs or syncytiotrophoblasts (n = 5) demonstrated ELL2 and HK2 increased with differentiation (p < 0.0024, p < 0.0039 respectively). CXCL8 and HLA-DPB1 were downregulated (p < 0.030, p < 0.011 respectively). GATA6 and INTS6 increased with EVT differentiation only, and UPP1 reduced with syncytialisation. SERPINE3 was undetectable. Trophoblast side-population marker mRNA was measured in human placentas (< 34-weeks’ gestation; n = 78 preeclampsia, n = 30 FGR, and n = 18 gestation-matched controls). ELL2, HK2 and CXCL8 were elevated in preeclamptic (p = 0.0006, p < 0.0001, p = 0.0335 respectively) and FGR placentas (p = 0.0065, p < 0.0001, p = 0.0001 respectively) versus controls. Placental GATA6 was reduced in pregnancies with preeclampsia and FGR (p = 0.0014, p = 0.0146 respectively). Placental INTS6 was reduced with FGR only (p < 0.0001). This study identified the localisation of a unique trophoblast subset enriched for side-population markers. Aberrant expression of some side-population markers may indicate disruptions to unique trophoblast subtypes in placental insufficiency.Graphical

Reduction of cardiovascular complications during delivery hospitalization in patients undergoing bariatric procedures.

The global surge in obesity presents a significant health challenge, leading to increased adoption of bariatric surgery as an intervention. However, the correlation between bariatric surgery and cardiovascular outcomes during subsequent pregnancies remains unclear. The aim of our study was to determine the prevalence of cardiovascular complications during delivery hospitalizations in patients with bariatric procedure. We performed a retrospective analysis utilizing the National Inpatient Sample database to examine data from delivery admissions of pregnant women with obesity and a history of bariatric surgery. These admissions were identified using International Classification of Diseases (ICD) codes from 2009 to 2019. In comparing pregnant individuals who had undergone bariatric surgery with those with obesity but had no such surgical history, we assessed the prevalence of cardiovascular complications. Our study included 3,027,987 pregnancies in individuals with obesity and an additional 117,350 pregnancies following bariatric surgery. Compared to patients without bariatric surgery, post-surgery patients were older (32.84 years vs 29.02 years), primarily White (59.0%), and mostly treated in large urban hospitals. Cardiovascular outcomes showcased reduced odds of congestive heart failure [Adjusted odds ratios (AOR) 0.11, 95% confidence intervals (CI) 0.01-0.74], gestational hypertensive complications (AOR 0.55, 95% CI 0.53-0.59), and cardiac arrhythmia (AOR 0.76, 95% CI 0.64-0.89) in the post-surgery group, with no significant difference in peripartum cardiomyopathy rates (AOR 0.72, 95% CI 0.29-1.76) and no instances of stroke or acute MI. Perinatally, the surgery cohort had higher odds of preterm birth (AOR 1.30, 95% CI 1.24-1.38) and fetal growth restriction (AOR 2.47, 95% CI 2.32-2.63) but fewer incidents of being large for gestational-age (AOR 0.35, 95% CI 0.32-0.38). As bariatric surgery became increasingly recognized as a significant factor in certain complications, its prevalence among the study population increased from 2009 to 2019. In summary, our research indicates that bariatric surgery is associated with a decreased risk of cardiovascular complications during delivery. This study highlights how insights from bariatric surgery outcomes could shape clinical guidelines for managing obesity in pregnant women.

Low-molecular-weight heparin for the prevention of preeclampsia in high-risk pregnancies without thrombophilia: a systematic review and meta-analysis

ObjectivesTo systematically evaluate the efficacy of low molecular weight heparin (LMWH) to prevent preeclampsia in high risk pregnant women without thrombophilia.Search strategyPubMed, Embase and the Cochrane library were searched for articles published before 1st August 2022 using the combination keywords “preeclampsia”, “Low Molecular Weight Heparin”, “LMWH”, “Heparin, Low Molecular Weight”, “Dalteparin”, “Nadroparin”, and “Tinzaparin”. Selection criteria: Randomized controlled trials evaluating the use of LMWH in pregnant women at high risk of preeclampsia without thrombophilia.Data collection and analysisTen studies were included in the meta-analysis (1758 patients in total). Outcomes were expressed as relative risk (RR) with 95% confidence intervals (CI).ResultsLMWH reduced the incidence of PE (RR = 0.67; 95% CI = 0.50–0.90; P = 0.009) in high risk pregnant women without thrombophilia. Subgroup analysis found that the prophylactic effect of LMWH was only significant in studies using low-dose aspirin (LDA) as the primary intervention. The combination of LMWH and LDA was also effective for the prevention of preterm birth and fetal growth restriction, but had no effect on the incidence of placenta abruption.ConclusionFor women at high risk of developing preeclampsia without thrombophilia, the combination of LMWH and low-dose aspirin is effective for the prevention of preeclampsia, preterm birth and fetal growth restriction and is superior to LDA alone.

OC05.04: The added value of the cerebroplacental ratio in late preterm fetal growth restriction: a contemporary urban cohort in the USA

OC05.04: The added value of the cerebroplacental ratio in late preterm fetal growth restriction: a contemporary urban cohort in the USA

Growth Pattern of Preterm Neonates with Fetal Growth Restriction: A Prospective Cohort Study.

To compare the growth of preterm neonates with fetal growth restriction (FGR) and preterm neonates born appropriate-for-gestational-age (AGA) from birth to 12-18 mo of corrected age (CA). In this prospective cohort study, 85 preterm neonates with FGR and 85 gestation- and gender-matched AGA neonates were followed up from birth till 12-18 mo corrected age. Anthropometric indices were compared at specific time points and the risk factors for underweight status were analyzed. Mean gestational age of the cohort was 32.8 ± 2.1 wk. Mean birth weight was 1414 ± 248g in the FGR and 1806 ± 416g in AGA neonates. At 12-18 mo of corrected age, a significantly greater proportion of FGR infants were wasted (24.3% vs. 7.2%, P = 0.005). A greater proportion of FGR infants were underweight (27% vs. 17.4%, P = 0.11), stunted (41.9% vs. 36.2%, P = 0.30), and microcephalic (27% vs. 23.1%, P = 0.36), although the differences were not statistically significant. Significant catch-up growth from 40 wk postmenstrual age (PMA) to 12-18 mo corrected age in weight (52.8% vs. 13.1%, P <0.001) and length (37.9% vs. 8.7%, P <0.001) was observed in the FGR neonates. The z-score of weight for age at 3 mo (adjusted OR 0.65, 95% CI: 0.52-0.8; P <0.001), the median time to full feeds (aOR: 1.10, 95% CI: 1.04-1.15; P = 0.001), and hypothyroidism (aOR 2.44, 95% CI: 1.46-4.08; P = 0.001), were independent predictors of underweight status at 12-18 mo. At 12-18 mo of corrected age, a significantly greater proportion of preterm FGR neonates were wasted compared to AGA ones. The former also exhibited significantly greater catch-up growth than the latter.

Cardiovascular responses to mild perinatal asphyxia in growth-restricted preterm lambs.

Growth-restricted neonates have worse outcomes after perinatal asphyxia, with more severe metabolic acidosis than appropriately grown neonates. The cardiovascular physiology associated with fetal growth restriction (FGR) may alter their response to asphyxia. However, research on asphyxia in FGR is limited. Here we compared cardiovascular hemodynamics in preterm FGR and control lambs during mild perinatal asphyxia. We induced FGR in one twin at 89 days gestation (term 148 days), while the other served as a control. At 126 days gestation, lambs were instrumented to allow arterial blood pressure and regional blood flow recording, and then mild perinatal asphyxia was induced by umbilical cord clamping, and resuscitation followed neonatal guidelines. FGR lambs maintained carotid blood flow (CBF) for 7 min, while control lambs rapidly decreased CBF (P < 0.05). Fewer growth-restricted lambs needed chest compressions for return of spontaneous circulation (ROSC) (17 vs. 83%, P = 0.02). The extent of blood pressure overshoot after ROSC was similar, but it took longer for MAP to return to baseline in FGR lambs (18.83 ± 0.00 vs. 47.67 ± 0.00 min, P = 0.003). Growth-restricted lambs had higher CBF after ROSC (P < 0.05) and displayed CBF overshoot, unlike control lambs (P < 0.03). In conclusion, preterm growth-restricted lambs show resilience during perinatal asphyxia based on prolonged CBF maintenance and reduced need for chest compressions during resuscitation. However, CBF overshoot after ROSC may increase the risk of cerebrovascular injury in FGR.NEW & NOTEWORTHY Preterm growth-restricted lambs maintain carotid blood flow for longer than control lambs during asphyxia and have a lower requirement for chest compressions than control lambs during resuscitation. Preterm growth-restricted, but not control, lambs displayed an overshoot in carotid blood flow following return of spontaneous circulation.

Early-Onset Fetal Growth Restriction Increases Left Ventricular Sphericity in Adolescents Born Very Preterm.

Left ventricular shape alterations predict cardiovascular outcomes and have been observed in children born preterm and after fetal growth restriction (FGR). The aim was to investigate whether left ventricular shape is altered in adolescents born very preterm and if FGR has an additive effect. Adolescents born very preterm due to verified early-onset FGR and two control groups with birthweight appropriate for gestational age (AGA), born at similar gestational age and at term, respectively, underwent cardiac MRI. Principal component analysis was applied to find the modes of variation best explaining shape variability for end-diastole, end-systole, and for the combination of both, the latter indicative of function. Seventy adolescents were included (13-16years; 49% males). Sphericity was increased for preterm FGR versus term AGA for end-diastole (36[0-60] vs -42[-82-8]; p = 0.01) and the combined analysis (27[-23-94] vs -51[-119-11]; p = 0.01), as well as for preterm AGA versus term AGA for end-diastole (30[-56-115] vs -42[-82-8]; p = 0.04), for end-systole (57[-29-89] vs -30[-79-34]; p = 0.03), and the combined analysis (44[-50-145] vs -51[-119-11]; p = 0.02). No group differences were observed for left ventricular mass or ejection fraction (all p ≥ 0.33). Sphericity was increased after very preterm birth and exacerbated by early-onset FGR, indicating an additive effect to that of very preterm birth on left ventricular remodeling. Increased sphericity may be a prognostic biomarker of future cardiovascular disease in this cohort that as of yetshows no signs of cardiac dysfunction using standard clinical measurements.

Involvement of oxidative stress in placental dysfunction, the pathophysiology of fetal death and pregnancy disorders.

Placental oxidative stress contributes to both normal and abnormal placentation during pregnancy. This review discusses the potential consequence of oxidative stress-induced placental dysfunction on pregnancies complicated by fetal death and pregnancies with a high risk of fetal death. The placenta is a source of reactive oxygen free radicals due to the oxidative metabolism required to meet the demands of the growing fetus. The placenta has an array of efficient antioxidant defense systems to deal with rising oxidative stress created by free radicals during pregnancy. Properly controlled physiological (low-level) free radical production is a necessary part of cellular signaling pathways and downstream activities during normal placental development; however, poorly controlled oxidative stress can cause aberrant placentation, immune disturbances and placental dysfunction. Abnormal placental function and immune disturbances are linked to many pregnancy-related disorders, including early and recurrent pregnancy loss, fetal death, spontaneous preterm birth, preeclampsia and fetal growth restriction. This review discusses the role of placental oxidative stress in both normal and pathological settings. Finally, based on previously published work, this review presents multiple lines of evidence for the strong association between oxidative stress and adverse pregnancy outcomes, including fetal death and pregnancies with a high risk of fetal death.

Placenta-associated adverse pregnancy outcomes in women experiencing mild or severe hyperemesis gravidarum – a systematic review and meta-analysis

BackgroundNausea and vomiting in pregnancy (NVP) affects 50–80% of pregnant women and is correlated to the level of human chorionic gonadotropin (hCG). Hyperemesis gravidarum (HG) is a severe condition, with an incidence of 0.2–1.5%, characterized by consistent nausea, vomiting, weight loss and dehydration continuing after the second trimester.AimThe aim of this systematic review was to investigate a potential correlation between NVP or HG with adverse pregnancy outcomes and hCG levels.MethodA systematic search in PubMed, Embase and CINAHL Complete was conducted. Studies on pregnant women with nausea in the first or second trimester, reporting either pregnancy outcomes or levels of hCG were included. The primary outcomes were preterm delivery (PTD), preeclampsia, miscarriage, and fetal growth restriction. Risk of bias was assessed using ROBINS-I. The overall certainty of evidence was assessed using GRADE.ResultsThe search resulted in 2023 potentially relevant studies; 23 were included. The evidence was uncertain for all outcomes, however women with HG had a tendency to have an increased risk for preeclampsia [odds ratio (OR) 1.18, 95% confidence of interval (CI) 1.03 to 1.35], PTD [OR 1.35, 95% CI 1.13 to 1.61], small for gestational age (SGA) [OR 1.24, 95% CI 1.13 to 1.35], and low birth weight (LBW) [OR 1.35, 95% CI 1.26 to 1.44]. Further, a higher fetal female/male ratio was observed [OR 1.36, 95% CI 1.15 to 1.60]. Meta-analyses were not performed for women with NVP; however, most of these studies indicated that women with NVP have a lower risk for PTD and LBW and a higher risk for SGA, and a higher fetal female/male ratio.ConclusionThere may be an increased risk in women with HG and a decreased risk in women with NVP for adverse placenta-associated pregnancy outcomes, however the evidence is very uncertain.Trial registrationPROSPERO: CRD42021281218.

Growth variables and obstetrical risk factors in newborns are associated with psychomotor development at preschool age

Low birthweight resulting from preterm birth or fetal growth restriction is associated with poor neurocognitive development and child psychopathology affecting school performance and educational success. Prediction of developmental performance may therefore serve as a basis for early intervention strategies to improve educational success and mental health of our children in a timely manner. This study aimed to explore the predictive capacity of morphometric variables taken at birth and that of obstetrical risk factors to predict developmental performance at 4.3 (standard deviation, 0.8) years preschool age. We examined predicted Total psychomotor development score, predicted Developmental disability index, calculated Morphometric vitality index, and predicted Intelligence quotient, Maze test, and Neurologic examination optimality score in a large prospective screening (cranial ultrasound screening, n=5,301) and validation cohort (n=508,926). In a single-center cohort observational study design (data collection done from 1984-1988, analysis done in 2022), a prospective cranial ultrasound screening study (1984-1988) was carried out on 5,301 live-born infants, including 571 (10.8%) preterm infants (≤36 weeks gestation), on the day of discharge of the mother at 5 to 8 days postpartum from a level 3 perinatal center. Predicted psychomotor development as assessed by predicted Total psychomotor development score, predicted Developmental disability index, calculated Morphometric vitality index, and predicted Intelligence quotient, Maze test, and Neurologic examination optimality score, was calculated. We related growth variables and obstetrical risk factors to Psychomotor development indices, and calculated Morphometric vitality index using odds ratios, receiver operating characteristics, analysis of variance, and multivariate analysis of variance. The key result of our study is the observation that simple morphometric measures from newborns at birth like weight/head circumference ratio predict overall psychomotor development at 4.3 years (standard deviation, 0.8) of preschool age. Psychomotor development was assessed by predicted Total psychomotor development score, predicted Intelligence quotient, Maze test, and Neurologic examination optimality score, and related to weight/head circumference ratio in linear regression (P<.001) and ROC curve analyses (P<.001). Further, white matter damage strongly predicted adverse outcome in predicted Developmental disability index (P<.001). There was also a close correlation between calculated Morphometric vitality index and predicted Developmental disability index (P<.001). Finally, brain body weight ratio, weight/head circumference ratio, preterm birth, reduced Apgar at 10 minutes, weight/length ratio, and white matter damage yielded highest odds ratios for adverse outcome in predicted Total psychomotor development score and in predicted Developmental disability index (P<.001) and high effect sizes in reduced predicted Intelligence quotient, Maze test, and Neurologic examination optimality scores. Simple morphometric data, birth variables, and obstetrical risk factors bear predictive capacity for neurocognitive performance in children at 4.3 years (standard deviation, 0.8) of age and hence provide a basis for parental consultation and early intervention to improve school performance, educational success, and mental health in developed and developing countries.

Mode of delivery and neonatal outcomes with early preterm severe preeclampsia: does fetal growth restriction matter?

Objective Severe preeclampsia diagnosed at or prior to 34 weeks is an indication for preterm delivery. Many patients with severe preeclampsia develop fetal growth restriction as a result of the placental dysfunction associated with both conditions. The ideal mode of delivery in cases of preterm severe preeclampsia with fetal growth restriction remains controversial, with providers often proceeding directly to cesarean delivery rather than attempting a trial of labor due to theoretic concerns about the harms of labor in the face of placental dysfunction. There are limited data supporting this approach. This study evaluates whether the presence of fetal growth restriction affects the ultimate mode of delivery or neonatal outcomes among pregnancies with severe preeclampsia undergoing induction of labor at or before 34 weeks. Methods This was a retrospective cohort study of singletons with severe preeclampsia undergoing induction of labor ≤ 34 weeks at a single center between January 2015 and April 2022. The primary predictor was fetal growth restriction, defined as estimated fetal weight < 10th percentile for gestational age on ultrasound. Mode of delivery and neonatal outcomes were compared between those with and without fetal growth restriction using Fisher’s exact and Kruskal-Wallis tests, and multivariate logistic regression was used to obtain adjusted odds ratios. Results 159 patients were included (N = 117 without fetal growth restriction, N = 42 with fetal growth restriction). There was no difference in vaginal delivery between the groups (70% vs 67%, p = .70). While those with fetal growth restriction had a higher incidence of respiratory distress syndrome and longer neonatal hospital stay, these differences were not statistically significant after adjusting for gestational age at delivery. There were no significant differences in other neonatal outcomes, including Apgar score, cord blood gases, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, and neonatal demise. Conclusion For pregnancies complicated by severe preeclampsia that require delivery ≤ 34 weeks, the likelihood of successful vaginal delivery following induction of labor does not differ based on presence of fetal growth restriction. Furthermore, fetal growth restriction is not an independent risk factor for adverse neonatal outcomes in this population. Induction of labor should be considered a reasonable approach and should be routinely offered to patients with concurrent preterm severe preeclampsia and fetal growth restriction.

Infant factors that impact the ecology of human milk secretion and composition—a report from “Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)” Working Group 3

Infants drive many lactation processes and contribute to the changing composition of human milk through multiple mechanisms. This review addresses the major topics of milk removal; chemosensory ecology for the parent–infant dyad; the infant’s inputs into the composition of the human milk microbiome; and the impact of disruptions in gestation on the ecology of fetal and infant phenotypes, milk composition, and lactation. Milk removal, which is essential for adequate infant intake and continued milk synthesis through multiple hormonal and autocrine/paracrine mechanisms, should be effective, efficient, and comfortable for both the lactating parent and the infant. All 3 components should be included in the evaluation of milk removal. Breastmilk “bridges” flavor experiences in utero with postweaning foods, and the flavors become familiar and preferred. Infants can detect flavor changes in human milk resulting from parental lifestyle choices, including recreational drug use, and early experiences with the sensory properties of these recreational drugs impact subsequent behavioral responses. Interactions between the infant’s own developing microbiome, that of the milk, and the multiple environmental factors that are drivers—both modifiable and nonmodifiable—in the microbial ecology of human milk are explored. Disruptions in gestation, especially preterm birth and fetal growth restriction or excess, impact the milk composition and lactation processes such as the timing of secretory activation, adequacy of milk volume and milk removal, and duration of lactation. Research gaps are identified in each of these areas. To assure a sustained and robust breastfeeding ecology, these myriad infant inputs must be systematically considered.

Neonatal outcomes following early fetal growth restriction: a subgroup analysis of the EVERREST study

ObjectiveTo quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR).DesignThe EVERREST (Does vascular endothelial growth factor gene therapy safely improve outcome in...

Elevated levels of renal function tests conferred increased risks of developing various pregnancy complications and adverse perinatal outcomes: insights from a population-based cohort study.

Physiological changes during pregnancy can affect the results of renal function tests (RFTs). In this population-based cohort study, we aimed to establish trimester-specific reference intervals (RIs) of RFTs in singleton and twin pregnancies and systematically investigate the relationship between RFTs and adverse pregnancy outcomes. The laboratory results of the first- and third-trimester RFTs, including blood urea nitrogen (BUN), serum uric acid (UA), creatinine (Crea) and cystatin C (Cys C), and the relevant medical records, were retrieved from 29,328 singleton and 840 twin pregnant women who underwent antenatal examinations from November 20, 2017 to January 31, 2021. The trimester-specific RIs of RFTs were estimated with both of the direct observational and the indirect Hoffmann methods. The associations between RTFs and pregnancy complications as well as perinatal outcomes were assessed by logistic regression analysis. Maternal RFTs showed no significant difference between the direct RIs established with healthy pregnant women and the calculated RIs derived from the Hoffmann method. In addition, elevated levels of RFTs were associated with increased risks of developing various pregnancy complications and adverse perinatal outcomes. Notably, elevated third-trimester RFTs posed strong risks of preterm birth (PTB) and fetal growth restriction (FGR). We established the trimester-specific RIs of RFTs in both singleton and twin pregnancies. Our risk analysis findings underscored the importance of RFTs in identifying women at high risks of developing adverse complications or outcomes during pregnancy.

Transcriptomics-Based Subphenotyping of the Human Placenta Enabled by Weighted Correlation Network Analysis in Early-Onset Preeclampsia With and Without Fetal Growth Restriction.

Placental disorders contribute to pregnancy complications, including preeclampsia and fetal growth restriction (FGR), but debate regarding their specific pathobiology persists. Our objective was to apply transcriptomics with weighted gene correlation network analysis to further clarify the placental dysfunction in these conditions. We performed RNA sequencing with weighted gene correlation network analysis using human placental samples (n=30), separated into villous tissue and decidua basalis, and clinically grouped as follows: (1) early-onset preeclampsia (EOPE)+FGR (n=7); (2) normotensive, nonanomalous preterm FGR (n=5); (2) EOPE without FGR (n=8); (4) spontaneous idiopathic preterm birth (n=5) matched for gestational age; and (5) uncomplicated term births (n=5). Our data was compared with RNA sequencing data sets from public databases (GSE114691, GSE148241, and PRJEB30656; n=130 samples). We identified 14 correlated gene modules in our specimens, of which most were significantly correlated with birthweight and maternal blood pressure. Of the 3 network modules consistently predictive of EOPE±FGR across data sets, we prioritized a coexpression gene group enriched for hypoxia-response and metabolic pathways for further investigation. Cluster analysis based on transcripts from this module and the glycolysis/gluconeogenesis metabolic pathway consistently distinguished a subset of EOPE±FGR samples with an expression signature suggesting modified tissue bioenergetics. We demonstrated that the expression ratios of LDHA/LDHB and PDK1/GOT1 could be used as surrogate indices for the larger panels of genes in identifying this subgroup. We provide novel evidence for a molecular subphenotype consistent with a glycolytic metabolic shift that occurs more frequently but not universally in placental specimens of EOPE±FGR.