Obesogenic diet in pregnancy disrupts placental iron handling and ferroptosis and stress signalling in association with fetal growth alterations.

Obesity and gestational diabetes (GDM) impact fetal growth during pregnancy. Iron is an essential micronutrient needed for energy-intense feto-placental development, but if mis-handled can lead to oxidative stress and ferroptosis (iron-dependent cell death). In a mouse model showing maternal obesity and glucose intolerance, we investigated the association of materno-fetal iron handling and placental ferroptosis, oxidative damage and stress signalling activation with fetal growth. Female mice were fed a standard chow or high fat, high sugar (HFHS) diet during pregnancy and outcomes were measured at day (d)16 or d19 of pregnancy. In HFHS-fed mice, maternal hepcidin was reduced and iron status maintained (tissue iron levels) at both d16 and d19. However, fetal weight, placental iron transfer capacity, iron deposition, TFR1 expression and ERK2-mediated signalling were reduced and oxidative damage-related lipofuscin accumulation in the placenta was increased in HFHS-fed mice. At d19, whilst TFR1 remained decreased, fetal weight was normal and placental weight, iron content and iron transporter genes (Dmt1, Zip14, and Fpn1) were reduced in HFHS-fed mice. Furthermore, there was stress kinase activation (increased phosphorylated p38MAPK, total ERK and JNK) in the placenta from HFHS-fed mice at d19. In summary, a maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of placental iron transporters in HFHS mice may protect the fetus from excessive oxidative iron. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity.

Impact of adenomyosis on pregnancy outcomes: a retrospective consecutive cohort study.

OBJECTIVE: This retrospective study explored the potential connection between adenomyosis and pregnancy outcomes. PATIENTS AND METHODS: A study included data from a total of 1,208 pregnancies. The adenomyosis group included 334 pregnant women with adenomyosis, and women in the control group (n=874) had uncomplicated pregnancies. Data on pregnancy complications and maternal and neonatal outcomes were compared. RESULTS: The incidence of gestational hypertension, gestational diabetes, and placenta previa was higher in the adenomyosis group compared to the control group (p<0.05). Adenomyosis was linked to a higher risk of postpartum hemorrhage (1,000-1,500 ml) but a lower risk of premature rupture of membranes (PROM) (p<0.05). Diagnosis of adenomyosis correlated with increased incidence of low fetal weight (20.3% vs. 21.3%, p<0.05) and a low APGAR score at 1 min (p<0.05). CONCLUSIONS: Adenomyosis correlated with a higher incidence of gestational hypertension, placenta previa, and gestational diabetes. At the same time, adenomyosis correlated with a significantly lower incidence of PROM compared to uncomplicated pregnancy. There was a significant increase in the incidence of postpartum hemorrhage and a higher risk of low fetal weight and lower APGAR score at 1 min in pregnancies with adenomyosis.

Evaluation of angiogenic factors in prediction of growth-related neonatal morbidity at term and comparison with competing-risks model.

OBJECTIVES: First, to describe the distribution of biomarkers of impaired placentation in small-for-gestational-age (SGA) pregnancies with neonatal morbidity; second, to examine the predictive performance for growth-related neonatal morbidity of a high soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio or low PlGF; and, third, to compare the performance of a high sFlt-1/PlGF ratio or low PlGF with that of the competing-risks model for SGA in predicting growth-related neonatal morbidity. METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, an ultrasound scan and measurement of serum PlGF and sFlt-1. The primary outcome was delivery within 4 weeks after assessment and at < 42 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt-1/PlGF ratio > 90th percentile, sFlt-1/PlGF ratio > 38 and the competing-risks model for SGA, using combinations of maternal risk factors and Z-scores of estimated fetal weight (EFW) with multiples of the median values of uterine artery pulsatility index, PlGF and sFlt-1, were estimated. The detection rates by the different methods of screening were compared using McNemar's test. RESULTS: In the study population of 29 035 women, prediction of growth-related neonatal morbidity at term provided by the competing-risks model was superior to that of screening by low PlGF concentration or a high sFlt-1/PlGF concentration ratio. For example, at a screen-positive rate (SPR) of 13.1%, as defined by the sFlt-1/PlGF ratio > 38, the competing-risks model using maternal risk factors and EFW predicted 77.5% (95% CI, 71.7-83.3%) of SGA < 10th percentile and 89.3% (95% CI, 83.7-94.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 71.4% (95% CI, 56.5-86.4%) and 90.0% (95% CI, 76.9-100%). These were significantly higher than the respective values of 41.0% (95% CI, 34.2-47.8%) (P < 0.0001), 48.8% (95% CI, 39.9-57.7%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.035) achieved by the application of the sFlt-1/PlGF ratio > 38. At a SPR of 10.0%, as defined by PlGF < 10th percentile, the competing-risks model using maternal factors and EFW predicted 71.5% (95% CI, 65.2-77.8%) of SGA < 10th percentile and 84.3% (95% CI, 77.8-90.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 68.6% (95% CI, 53.1-83.9%) and 85.0% (95% CI, 69.4-100%). These were significantly higher than the respective values of 36.5% (95% CI, 29.8-43.2%) (P < 0.0001), 46.3% (95% CI, 37.4-55.2%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.021) achieved by the application of PlGF < 10th percentile. CONCLUSION: At 36 weeks' gestation, the prediction of growth-related neonatal morbidity by the competing-risks model for SGA, using maternal risk factors and EFW, is superior to that of a high sFlt-1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Validation of Fetal Medicine Foundation competing-risks model for small-for-gestational-age neonate in early third trimester.

OBJECTIVE: To evaluate the new 36-week Fetal Medicine Foundation (FMF) competing-risks model for the prediction of small-for-gestational age (SGA) at an earlier gestation of 30 + 0 to 34 + 0 weeks. METHODS: This was a retrospective multicenter cohort study of prospectively collected data on 3012 women with a singleton pregnancy undergoing ultrasound examination at 30 + 0 to 34 + 0 weeks' gestation as part of a universal screening program. We used the default FMF competing-risks model for prediction of SGA at 36 weeks' gestation combining maternal factors (age, obstetric and medical history, weight, height, smoking status, race, mode of conception), estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI) to calculate risks for different cut-offs of birth-weight percentile and gestational age at delivery. We examined the accuracy of the model by means of discrimination and calibration. RESULTS: The prediction of SGA < 3rd percentile improved with the addition of UtA-PI and with a shorter examination-to-delivery interval. For a 10% false-positive rate, maternal factors, EFW and UtA-PI predicted 88.0%, 74.4% and 72.8% of SGA < 3rd percentile delivered at < 37, < 40 and < 42 weeks' gestation, respectively. The respective values for SGA < 10th percentile were 86.1%, 69.3% and 66.2%. In terms of population stratification, if the biomarkers used are EFW and UtA-PI and the aim is to detect 90% of SGA < 10th percentile, then 10.8% of the population should be scanned within 2 weeks after the initial assessment, an additional 7.2% (total screen-positive rate (SPR), 18.0%) should be scanned within 2-4 weeks after the initial assessment and an additional 11.7% (total SPR, 29.7%) should be examined within 4-6 weeks after the initial assessment. The new model was well calibrated. CONCLUSIONS: The 36-week FMF competing-risks model for SGA is also applicable and accurate at 30 + 0 to 34 + 0 weeks and provides effective risk stratification, especially for cases leading to delivery < 37 weeks of gestation. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Lung Hypoplasia in Fetuses with Skeletal Dysplasia Determined by Fetal Lung Weight: Which Ultrasound Measurement/Ratio Has the Highest Detection Rate.

INTRODUCTION: To determine lung hypoplasia in cases with fetal skeletal dysplasia based on the total lung weight at autopsy as the most accountable surrogate marker for pulmonary hypoplasia. METHODS: This retrospective cohort study included all pregnancies with antenatal diagnosis of skeletal dysplasia (2012-2018). We included only cases in which information on fetal biometry was available within 2 weeks before delivery and had autopsy and skeletal X-rays + molecular analysis using extracted fetal DNA. We compared the predictive accuracy of fetal sonographic body-proportional ratios (BPRs) including: (1) thoracic circumference-to-abdominal circumference ratio, (2) the femur length-to-abdominal circumference (FL/AC) ratio, (3) head circumference-to-abdominal circumference ratio, and (4) foot length-to-femur length ratio. Lung hypoplasia was defined as total lung weight below -2 SD from the expected mean for gestational age. RESULTS: Fifty three pregnancies with antenatal diagnosis of skeletal dysplasia underwent autopsy included. Lung hypoplasia was determined in 34 (64.1%). Median of gestational age at last sonographic assessment was 21.3 (19.9-24.9) weeks. FL/AC ratio demonstrated the highest area under the curve of 0.817 (95% CI: 0.685-0.949; p < 0.0001). FL/AC ≤0.1550 demonstrated the highest detection rate of 88.2% along with the highest negative predictive value of 75%. CONCLUSION: Using a novel, more practical approach to predict lung hypoplasia in skeletal dysplasia, fetal sonographic BPRs and, specifically, FL/AC ratio demonstrate a high detection rate of lung hypoplasia.

Trimester-Specific Urinary Strontium Concentrations during Pregnancy and Longitudinally Assessed Fetal Growth: Findings from a Prospective Cohort.

BACKGROUND: Studies have claimed that strontium (Sr) is associated with fetal growth, but the research evidence is insufficient. OBJECTIVES: Our study aimed to evaluate associations of trimester-specific urinary Sr concentrations with fetal growth parameters and birth size indicators. METHODS: In this prospective cohort, 9015 urine samples (first trimester: 3561, 2nd trimester: 2756, 3rd trimester: 2698) from 3810 mothers were measured for urinary Sr levels using inductively coupled plasma mass spectrometry (ICP-MS) and adjusted to urine specific gravity. We calculated standard deviation scores (SD-scores) for ultrasound-measured fetal growth parameters (head circumference, abdominal circumference, femur length, and estimated fetal weight) at 16, 24, 31, and 37 wk of gestation and birth size indicators (birth weight, birth length, and Ponderal index). Generalized linear models and generalized estimating equations models were used. Models were adjusted for potential covariates (gestational age, maternal age, body mass index, parity, passive smoking during pregnancy, education, folic acid supplements use, physical activity, maternal and paternal height, and infant sex). RESULTS: Positive associations of naturally logarithm-transformed Sr concentrations with fetal growth parameters and birth size indicators were observed. With each doubling increase in the urinary ln-Sr level in all 3 trimesters resulting in a percent change in SD-scores fetal growth parameters at 24, 31, and 37 wk of gestation and birth size indicators, 5.09%-8.23% in femur length, 7.57%-11.53% in estimated fetal weight, 6.56%-10.42% in abdominal circumference, 6.25% in head circumference, 5.15%-7.85% in birth weight, and 5.71%-9.39% in birth length, respectively. Most of the above statistical results could only be observed in male fetuses. CONCLUSIONS: Our findings suggest a potential association between Sr concentration and increased fetal growth, but these results and underlying mechanisms need further confirmation and clarification.

Repercusión del síndrome metabólico sobre el crecimiento de fetos de ratas Wistar / Repercussion of the metabolic syndrome on the growth of Wistar rat fetuses

Introducción: El síndrome metabólico es un conjunto de anomalías metabólicas como obesidad, dislipidemia, intolerancia a la glucosa e hipertensión arterial. Se realizó estudio experimental, longitudinal prospectivo en la Unidad de Toxicología Experimental de Villa Clara, periodo septiembre del 2016 y julio del 2019. Objetivo: Evaluar las modificaciones del crecimiento de los fetos de ratas con síndrome metabólico, con respecto al grupo control. Métodos: Se crearon dos grupos, uno de control y otro de estudio con síndrome metabólico inducido. Las variables estudiadas fueron: peso, talla y diámetros craneanos. Se utilizó el programa Excel 2010 y el SPSS versión 15.0 para Windows, la prueba Chi Cuadrado, y como estadístico de decisión, la significación de Monte Carlo. Resultados: Los fetos de ratas con síndrome metabólico inducido tuvieron mayor peso y talla. Conclusiones: El síndrome metabólico influyó en la ganancia del peso y la talla en los fetos en vida prenatal, al incrementar la probabilidad de macrosomía al momento del nacimiento.

Introduction: metabolic syndrome is a group of metabolic abnormalities such as obesity, dyslipidemia, glucose intolerance and arterial hypertension. An experimental, longitudinal and prospective study was carried out in the Villa Clara Experimental Toxicology Unit from September 2016 to July 2019. Objective: to evaluate the changes in the growth of rat fetuses with metabolic syndrome, with respect to the control group. Methods: two groups with induced metabolic syndrome were created, one for control and the other for study. Weight, height and cranial diameters were the studied variables. The Excel 2010 program and SPSS version 15.0 for Windows and the Chi Square test were used, as well as the Monte Carlo significance as statistical decision. Results: rat fetuses with induced metabolic syndrome had greater weight and height. Conclusions: the metabolic syndrome influenced the weight and height gain in prenatal fetuses, increasing the probability of macrosomia at birth.

A study of protective effects of Mus81 in preeclampsia.

This study was to investigate the effect and mechanism of Mus81 in severe PE. 20 cases of pregnant women with severe PE and 20 cases of healthy pregnant women were enrolled. Placental tissues were collected after delivery, and the expression of Mus81 in placental tissues was detected by qRT-PCR and Western blot (WB). The si-Mus81 adenovirus was used to construct a pregnant mouse model of Mus81 down-expression in vivo, to clarify the effect of Mus81 on pregnant mice and blood pressure, urinary protein, serum sFLT1 and fetal weight in PE. After overexpression of Mus81 in HTRB-S/Vneo cells, the proliferation, migration and apoptosis of the cells were measured by EdU staining, flowcytometry, qRT-PCR and cell scratch test. Protein expression of the Wnt/ß-catenin signaling pathway was detected by WB. To further explore the mechanism, Wnt/ß-catenin inhibitor DKK1 inhibitor was added to HTRB-S/Vneo cells and then Ad-Mus81 was added for co-incubation for 48 h. Protein expressions p-ß-catenin and activated-ß-catenin were detected by WB. Bax and Bcl-2 were detected by qRT-PCR, and the proliferation of HTRB-S/Vneo cells was measured by EdU staining. Cell migration was detected by scratch test. The expression of Mus81 in the placental tissues of pregnant women with severe PE was lower than that in normal placental tissues. The blood pressure, urine protein and serum sFLT1 protein levels of Mus81 knockdown mice were all upregulated and the fetal weight was decreased after the injection of si-Mus81, which successfully simulated the characteristics of PE. After overexpression of Mus81, the proliferation and migration of HTRB-S/Vneo cells were enhanced, while the apoptosis was decreased. After overexpression of Mus81, the expression levels of p-ß-catenin decreased while active-ß-catenin increased obviously. Then, DKK1 inhibitor and Ad-Mus81 were added to the HTRB-S/Vneo cells and co-incubated for 48 h. Compared with the Ad-Mus81+DMSO group, the expression of p-ß-catenin increased while activated-ß-catenin decreased in the Ad-Mus81+DKK1 inhibitor group. The proliferation and migration decreased, but apoptosis of HTRB-S/Vneo cells was increased. Mus81 can regulate the proliferation, migration and apoptosis of trophoblast cells through the Wnt/ß-catenin pathway, which plays an important role in maintaining the normal physiological function of trophoblast cells and is also involved in the occurrence and development of severe PE.

[Association between maternal plasma one-carbon biomarkers during pregnancy and fetal growth in twin pregnancies].

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (ß=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (ß=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.

Fetal Growth Retardation is Associated with High Apoptotic Cells and Low VEGF Expression in Placenta of Malarial Pregnant Mice.

Background: During pregnancy, pregnant women are susceptible to malaria, contributing significantly to maternal and infant mortality. Objective: This research was conducted to study the effect of Plasmodium berghei infection in pregnant mice on fetal growth retardation through placental cell apoptosis and the change of local vascularization. Methods: Eighteen pregnant Balb/c strain mice resulting from simultanously mating were divided into two groups those were nine pregnant mice used as non infected group and nine pregnant mice infected with Plasmodium berghei on day 9th post mating used as infected group respectively. On day 15th of post mating, all of the pregnant mice were killed. Fetal weights were measured using analytic balance. Apoptosis of placental cells and VEGF expression in the placental tissue were measured using immunohistochemistry. Results: Result showed that there was sequestration of parasite-infected red blood cells (PRBCs) in intervillous space. Statistical analysis showed that the fetal weights in infected pregnant mice group was significantly lower than non infected one (p = 0.01), and the placental cell apoptosis in placental tissue of infected pregnant mice was significantly higher than the non infected one (p=0.00).There was also a significant difference on VEGF expression between infected group and non infected group (p= 0,00). Conclusion: Plasmodium berghei infection in pregnant Balb/c mice can cause fetal growth retardation due to high of placental cell apoptosis and low VEGF expression.

Effects of Radiofrequency Electromagnetic Field (RF-EMF) exposure on pregnancy and birth outcomes: A systematic review of experimental studies on non-human mammals.

BACKGROUND: The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency electromagnetic field (RF-EMF) exposure and adverse health effects. Within the project, 6 topics have been prioritized by an expert group, which include reproductive health outcomes. OBJECTIVES: According to the protocol published in 2021, a systematic review and meta-analyses on the adverse effects of RF-EMF exposure during pregnancy in offspring of experimental animals were conducted. METHODS: Three electronic databases (PubMed, Scopus and EMF Portal) were last searched on September 8 or 17, 2022. Based on predefined selection criteria, the obtained references were screened by two independent reviewers. Studies were included if they met the following criteria: 1) original, sham controlled experimental study on non-human mammals exposed in utero, published in peer-reviewed journals, 2) the experimental RF-EMF exposure was within the frequency range 100 kHz-300 GHz, 3) the effects of RF-EMF exposure on fecundity (litter size, embryonic/fetal losses), on the offspring health at birth (decrease of weight or length, congenital malformations, changes of sex ratio) or on delayed effects (neurocognitive alterations, female infertility or early-onset cancer) were studied. Study characteristics and outcome data were extracted by two reviewers. Risk of bias (RoB) was assessed using the Office of Health Assessment and Translation (OHAT) guidelines. Study results were pooled in a random effects meta-analysis comparing average exposure to no-exposure and in a dose-response meta-analysis using all exposure doses, after exclusion of studies that were rated at "high concern" for RoB. Subgroup analyses were conducted for species, Specific Absorption Rate (SAR) and temperature increase. The certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: Eighty-eight papers could be included in this review. Effects on fecundity. The meta-analysis of studies on litter size, conducted at a whole-body average SAR of 4.92 W/kg, did not show an effect of RF-EMF exposure (MD 0.05; 95% CI -0.21 to 0.30). The meta-analysis of studies on resorbed and dead fetuses, conducted at a whole-body average SAR of 20.26 W/kg, showed a significant increase of the incidence in RF-EMF exposed animals (OR 1.84; 95% CI 1.27 to 2.66). The results were similar in the dose-response analysis. Effects on the offspring health at birth. The meta-analysis of studies on fetal weight, conducted at a whole-body average SAR of 9.83 W/kg, showed a small decrease in RF-EMF exposed animals (SMD 0.31; 95% CI 0.15 to 0.48). The meta-analysis of studies on fetal length, conducted at a whole-body average SAR of 4.55 W/kg, showed a moderate decrease in length at birth (SMD 0.45; 95% CI 0.07 to 0.83). The meta-analysis of studies on the percentage of fetuses with malformations, conducted at a whole-body average SAR of 6.75 W/kg, showed a moderate increase in RF-EMF exposed animals (SMD -0.45; 95% CI -0.68 to -0.23). The meta-analysis of studies on the incidence of litters with malformed fetuses, conducted at a whole-body average SAR of 16.63 W/kg, showed a statistically significant detrimental RF-EMF effect (OR 3.22; 95% CI 1.9 to 5.46). The results were similar in the dose-response analyses. Delayed effects on the offspring health. RF-EMF exposure was not associated with detrimental effects on brain weight (SMD 0.10; 95% CI -0.09 to 0.29) and on learning and memory functions (SMD -0.54; 95% CI -1.24 to 0.17). RF-EMF exposure was associated with a large detrimental effect on motor activity functions (SMD 0.79; 95% CI 0.21 to 1.38) and a moderate detrimental effect on motor and sensory functions (SMD -0.66; 95% CI -1.18 to -0.14). RF-EMF exposure was not associated with a decrease of the size of litters conceived by F2 female offspring (SMD 0.08; 95% CI -0.39 to 0.55). Notably, meta-analyses of neurobehavioural effects were based on few studies, which suffered of lack of independent replication deriving from only few laboratories. DISCUSSION: There was high certainty in the evidence for a lack of association of RF-EMF exposure with litter size. We attributed a moderate certainty to the evidence of a small detrimental effect on fetal weight. We also attributed a moderate certainty to the evidence of a lack of delayed effects on the offspring brain weight. For most of the other endpoints assessed by the meta-analyses, detrimental RF-EMF effects were shown, however the evidence was attributed a low or very low certainty. The body of evidence had limitations that did not allow an assessment of whether RF-EMF may affect pregnancy outcomes at exposure levels below those eliciting a well-known adverse heating impact. In conclusion, in utero RF-EMF exposure does not have a detrimental effect on fecundity and likely affects offspring health at birth, based on the meta-analysis of studies in experimental mammals on litter size and fetal weight, respectively. Regarding possible delayed effects of in utero exposure, RF-EMF probably does not affect offspring brain weight and may not decrease female offspring fertility; on the other hand, RF-EMF may have a detrimental impact on neurobehavioural functions, varying in magnitude for different endpoints, but these last findings are very uncertain. Further research is needed on the effects at birth and delayed effects with sample sizes adequate for detecting a small effect. Future studies should use standardized endpoints for testing prenatal developmental toxicity and developmental neurotoxicity (OECD TG 414 and 426), improve the description of the exposure system design and exposure conditions, conduct appropriate dosimetry characterization, blind endpoint analysis and include several exposure levels to better enable the assessment of a dose-response relationship. PROTOCOL REGISTRATION AND PUBLICATION: The protocol was published in Pacchierotti et al., 2021 and registered in PROSPERO CRD42021227746 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227746).

Subfertility versus ART: unraveling the origins of fetal cardiac programming.

STUDY QUESTION: Do spontaneously conceived (SC) fetuses from subfertile couples show the same signs of cardiac remodeling as those observed after IVF treatments? SUMMARY ANSWER: As opposed to fetuses from IVF, SC fetuses from subfertile couples do not show cardiac remodeling and present a similar cardiac structure and function to those of SC fetuses from fertile couples. WHAT IS KNOWN ALREADY: Subjects conceived by IVF present signs of cardiac remodeling and suboptimal function in utero and during childhood, including larger atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation as compared to SC individuals from fertile couples. There are no previous publications investigating the independent cardiac programming effects of infertility in SC fetuses from subfertile couples (with time-to-pregnancy (TTP) over 12 months). STUDY DESIGN, SIZE, DURATION: A prospective cohort study of 289 singleton pregnancies exposed and not exposed to subfertility recruited from 2019 to 2021, including 96 SC pregnancies from fertile couples (TTP under 12 months), 97 SC from subfertile couples (TTP over 12 months), and 96 from IVF after fresh embryo transfer. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. The overall attrition rate was 15.7%. PARTICIPANTS/MATERIALS, SETTING, METHODS: SC from subfertile couples and IVF pregnancies were identified as eligible at pregnancy diagnosis, and eligible SC pregnancies from fertile couples who attended our maternal-fetal unit were invited to participate at third trimester, being matched to the other groups by maternal age. Fetal echocardiography was performed at 29-34 weeks of pregnancy to assess cardiac structure and function, and results were adjusted by parental age, maternal smoking status, child's birth order, birthweight centile, gestational age, and estimated fetal weight at scan. MAIN RESULTS AND THE ROLE OF CHANCE: Parental age, ethnicity, BMI, and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or etiology between the subfertile and the IVF populations (TTP: subfertile median 35 months (interquartile range 20-48) versus IVF: 47 (25-61); P-value = 0.051). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% (SD 3.4) versus subfertile 17.8% (3.5) versus fertile 17.6% (3.3); adjusted P-value < 0.001), more globular ventricles (right ventricular sphericity index: IVF 1.56 (0.25) versus subfertile 1.72 (0.26) versus fertile 1.72 (0.26); <0.001), and thicker myocardial walls (relative wall thickness: IVF 0.86 (0.22) versus subfertile 0.64 (0.13) versus fertile 0.64 (0.18); <0.001). Whereas SC fetuses from fertile and subfertile couples had preserved cardiac function, IVF fetuses showed signs of suboptimal systolic and diastolic function, with reduced tricuspid ring displacement (IVF 7.26 mm (1.07) versus subfertile 8.04 mm (1.18) versus fertile 7.89 mm (1.51); <0.001) and increased left myocardial performance index (IVF 0.49 (0.08) versus subfertile 0.45 (0.09) versus fertile 0.45 (0.10); <0.001). A sub-analysis including only unexplained infertility cases in subfertile SC and IVF groups showed similar results. LIMITATIONS, REASONS FOR CAUTION: The fetal cardiac changes reported here are subclinical, and most of the cardiovascular parameters were within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: Subfertility per se does not seem to be associated to fetal cardiac remodeling, which has been previously described in IVF fetuses. Future studies are warranted to further investigate other factors related to the observed fetal cardiac changes associated with ART. STUDY FUNDING/COMPETING INTEREST(S): This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI16/00861, PI17/00675, PI18/00073, INT21/00027)-co-funded by the European Union, Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant no 1531. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Relación entre biometría fetal, producto de acumulación de los lípidos y condición trófica al nacer / Relationship between fetal biometry, lipid accumulation product and the trophic condition at birth

Fundamento: Las alteraciones del estado nutricional materno generalmente se relacionan con desviaciones del crecimiento fetal, que pueden detectarse por los parámetros biofísicos fetales e identifican la posible condición trófica al nacer. Objetivo: Determinar la posible relación entre los parámetros biométricos fetales, la condición trófica al nacer y el producto de acumulación de los lípidos. Metodología: Se realizó un estudio transversal en el Policlínico Chiqui Gómez Lubian del municipio Santa Clara, durante el año 2019, en una población de 253 gestantes normopeso supuestamente sanas al inicio de la gestación. La muestra no probabilística fue de 144 gestantes. Las variables de estudio fueron: producto de acumulación de los lípidos, biometría fetal y condición trófica al nacer. Se utilizaron métodos teóricos, empíricos y estadísticos. Resultados: En el segundo trimestre ningún parámetro biométrico coincidió con la condición al nacer de pequeño, mientras que para el grande coincidieron las circunferencias cefálica y abdominal. En el tercer trimestre la longitud del fémur y la circunferencia abdominal coinciden en la identificación del pequeño y del grande. El PAL se correlacionó con la circunferencia abdominal del tercer trimestre y con el peso al nacer; presentando mayor frecuencia de valores en el tercer tertil para los nacimientos grandes. Conclusiones: La circunferencia abdominal fue el parámetro biométrico con mayor coincidencia con la condición trófica al nacer, la que se asoció con valores en el tercer tertil del PAL para la detección de nacimientos grandes, relacionándose el fenotipo normopeso metabólicamente obeso con el crecimiento fetal por exceso.

Background: Maternal nutritional status disorders are usually related to fetal growth deviations, which can be detected by fetal biophysical parameters and identify the possible trophic condition at birth. Objective: To determine the possible relationship between fetal biometric parameters, the birth trophic state and lipid accumulation product. Methodology: A cross-sectional study was conducted at the Chiqui Gómez Lubian Polyclinic in Santa Clara municipality, during 2019, in a population of 253 normal-weight pregnant women who were apparently healthy at the beginning of their gestation. The non-probability sample was made up of 144 pregnant women. Study variables were: lipid accumulation product, fetal biometry and trophic condition at birth. Theoretical, empirical and statistical methods were used. Results: In the second trimester, none of the biometric parameters matched the condition at birth as a small child, while in the large one the head and abdominal circumferences matched. In the third trimester, femoral length and abdominal circumference coincide in identifying the small one and the large one. LAP correlated with third trimester abdominal circumference and birth weight, presenting higher frequency of values in the third tertile for large births. Conclusions: Abdominal circumference was the biometric parameter with the highest coincidence with trophic condition at birth, associated with values in the third tertile of the LAP for detecting large births, relating the metabolically obese normal weight phenotype with excessive fetal growth.

Capacidad del diámetro biparietal para predecir los recién nacidos grandes para edad gestacional. Estudio de cohorte retrospectivo / Ability of biparietal diameter to predict large for gestational age newborns. A retrospective cohort study

Fundamento: Predecir el recién nacido grande para la edad gestacional es una acción de salud que necesita de herramientas tecnológicas de probada eficiencia. Objetivo: Determinar la capacidad predictiva del diámetro biparietal en los recién nacidos grandes para la edad gestacional. Metodología: Estudio de cohorte retrospectivo que incluyó 1959 gestantes cubanas con embarazo simple con captación y término del embarazo entre enero del 2009 y diciembre de 2017. En cada trimestre de gestación se compararon las condiciones tróficas adecuado para la edad gestacional (AEG) y grandes para la edad gestacional (GEG) mediante estadígrafos de tendencia central (media) y de dispersión (rango, desviación estándar) correspondientes al diámetro biparietal. Se calculó además el intervalo de confianza (IC) de 95 % para la diferencia de medias del diámetro biparietal. Asimismo, se realizó un análisis de curvas ROC para determinar si el diámetro biparietal y el peso fetal predicen la condición trófica grande para la edad gestacional en el segundo y tercer trimestre de gestación. Los datos fueron recogidos del libro registro de genética del área de salud. Resultados: El diámetro biparietal en el segundo y tercer trimestre de gestación tuvo un área bajo curva de 0.60 (IC 95 %: 0.54-0.65) y 0.59 (IC 95 %: 0.54-0.64) respectivamente. Los puntos de corte establecidos (T2: 56.55 mm, T3: 81.55 mm) tienen una especificidad y exactitud superior al 78 %. Conclusiones: El diámetro biparietal y los modelos de regresión de Shepard y de Hadlock V mostraron capacidad para discriminar el nacimiento grande para la edad gestacional del adecuado para la edad gestacional, a partir del segundo trimestre de gestación siendo más eficaces en el tercero.

Background: Predicting large for gestational age newborns is a medical action that requires technological tools with proven efficiency. Objective: To determine the predictive ability of biparietal diameter in large newborns for gestational age. Methodology: Retrospective cohort study that included 1959 Cuban pregnant women with a singleton pregnancy, with recruitment and pregnancy term between January 2009 and December 2017. In each gestational trimester, trophic conditions appropriate for gestational age (GAW) were compared and large for gestational age (GA) using central tendency (mean) and dispersion (range, standard deviation) statistics corresponding to the biparietal diameter. The 95% confidence interval (CI) for mean biparietal diameter difference was also calculated. In addition, an analysis of ROC curves was performed to determine if biparietal diameter and fetal weight predict large trophic condition for gestational age in the second and third gestational trimester. Data were gathered from the health area genetics registry book. Results: Biparietal diameter in the second and third trimester of gestation had an area under curve of 0.60 (95% CI: 0.54-0.65) and 0.59 (95% CI: 0.54-0.64) respectively. The established cut-off points (T2: 56.55 mm, T3: 81.55 mm) have a specificity and accuracy greater than 78%. Conclusions: Biparietal diameter and the Shepard and Hadlock V regression models showed ability to discriminate large for gestational age birth from adequate for gestational age birth from the second trimester of gestation onward, being more effective in the third trimester.

In utero effects of opioids on fetal growth.

BACKGROUND: Studies indicate antenatal opioid use is associated with birth size deficits, as evidenced by reductions in birth weight and head circumference. However, there remains a limited understanding of how early this growth restriction occurs, and what specific parameters are affected. This novel study evaluated global and specific growth deficits associated with prenatal opioid exposure between 18-22 weeks' gestation as assessed during anatomy ultrasounds. METHODS: Pregnant women who completed an anatomy ultrasound were identified via electronic medical records from a large academic obstetric practice. The study group used opioids, with tobacco and/or marijuana use permitted (n = 41). The control group could have used tobacco and/or marijuana, but not opioids (n = 308). Neither group had alcohol or other drug exposure. Records were reviewed for medical history and ultrasound size parameters, coded as percentiles for gestational age. RESULTS: Demographics and medical histories were compared with several significant differences noted. After controlling for these differences, significant (p < 0.05) growth deficits were identified in opioid-exposed fetuses. Specifically, reductions >10 percentile points were observed in head circumference, biparietal diameter, and humerus length for opioid-exposed fetuses compared to controls. Additionally, intrauterine growth restriction (IUGR) was diagnosed five times more often. Femur length was significantly reduced in opioid-exposed fetuses prior to adjustment for confounding (p = .016), but this reduction was not significant (p = .072) after controlling for background differences. Estimated fetal weight (p = .274) and abdominal circumference (p = .633) were not significantly different between exposure groups. CONCLUSION: Fetal opioid exposure predicted various bone growth deficits during routine anatomy ultrasound, indicating the effects of opioid exposure on size deficits may be evident as early as 18-22 weeks' gestation. These findings may also suggest that in utero opioid exposure negatively impacts bone growth specifically rather than weight or fat/muscle mass. Additional studies with larger sample sizes may also reveal significantly reduced femur length, further supporting a negative impact on bone growth. Future studies evaluating bone health and immune function in children after antenatal opioid exposure may help clarify this specific effect of opioids on bone development.

From Bariatric Surgery to Conception: The Ideal Timing to Optimize Fetal Weight.

PURPOSE: Bariatric surgery (BS) increases the risk of small for gestational age (SGA) neonates. Guidelines recommend postponing pregnancy for 12-24 months, but optimal surgery-to-conception interval (BSCI) remains uncertain. We aimed to evaluate the impact of BSCI on birth weight and SGA. MATERIALS AND METHODS: Retrospective cohort study of 42 pregnancies following BS, including Roux-en-Y gastric bypass, gastric sleeve, adjustable gastric banding and biliopancreatic diversion. Neonates were classified as SGA if birth weight < 10th percentile. Optimal BSCI was obtained from the analysis of ROC curves, and pregnancies were compared by that cut-off. RESULTS: There was a linear association between BSCI and birth weight and an inverse association with SGA, with each additional month of BSCI translating into additional 4.5 g (95%CI: 2.0-7.0) on birth weight and -6% risk of SGA (95%CI: 0.90-0.99). We established a cut-off of 24.5 months of BSCI for lower risk of SGA. Pregnancies conceived in the first 24 months had a more than tenfold increased risk of SGA (OR 12.6, 95%CI: 2.4-66.0), even when adjusted for maternal age, gestational diabetes and inadequate gestational weight gain. CONCLUSION: BSCI was associated with birth weight and SGA. Our results are in line with the recommendations of BSCI of at least 24 months to reduce the risk of SGA.

Subclassification of fetal growth restriction type IIa vs type IIb applied to twin-twin transfusion syndrome.

BACKGROUND: Subclassification of monochorionic twins with selective fetal growth restriction type II into IIa vs IIb has been proposed because of differing neonatal survival outcomes of the fetus with growth restriction after laser surgery based on preoperative Doppler findings in the middle cerebral artery and ductus venosus. There is substantial clinical overlap between selective fetal growth restriction and twin-twin transfusion syndrome. OBJECTIVE: This study aimed to compare donor twin neonatal survival after laser surgery in cases of twin-twin transfusion syndrome with concomitant donor fetal growth restriction type IIa vs IIb. STUDY DESIGN: This was a retrospective study of monochorionic multifetal pregnancies treated with laser surgery for stage III twin-twin transfusion syndrome and concomitant donor twin fetal growth restriction type II at a referral center from 2006 to 2021. Donor fetal growth restriction type II was defined as having an estimated fetal weight <10th percentile with persistent absent and/or reversed end-diastolic velocity in the umbilical artery. Moreover, patients were subclassified as type IIa (having normal middle cerebral artery peak systolic velocities and ductus venosus Doppler waveforms) vs type IIb (having middle cerebral artery peak systolic velocities ≥1.5 multiples of the median and/or ductus venosus with persistent absent or reversed atrial systolic flow). This study compared 30-day neonatal survival of the donor twin by fetal growth restriction type IIa vs IIb using logistic regression to adjust for relevant preoperative covariates (P<.10 in bivariate analysis). RESULTS: Of 919 patients who underwent laser surgery for twin-twin transfusion syndrome, 262 had sstage III donor or donor and recipient twin-twin transfusion syndrome; of these patients, 189 (20.6%) had concomitant donor fetal growth restriction type II. Moreover, 12 patients met the exclusion criteria, yielding 177 patients (19.3%) who composed the study cohort. Patients were subclassified as donor fetal growth restriction type IIa (146 [82%]) vs type IIb (31 [18%]). Donor neonatal survival for fetal growth restriction type IIa vs IIb was 71.2% vs 41.9% (P=.003). Recipient neonatal survival did not differ between the 2 types (P=1.000). Patients classified with twin-twin transfusion syndrome and concomitant donor fetal growth restriction type IIb were 66% less likely to have neonatal survival of the donor after laser surgery (adjusted odds ratio, 0.34; 95% confidence interval, 0.15-0.80; P=.0127). The logistic regression model was adjusted for gestational age at the procedure, estimated fetal weight percent discordance, and nulliparity. The c-statistic was 0.702. CONCLUSION: For patients with stage III twin-twin transfusion syndrome and concurrent donor fetal growth restriction with persistent absent or reversed end-diastolic velocity in the umbilical artery (ie, fetal growth restriction type II), subclassification into fetal growth restriction type IIb based on elevated middle cerebral artery peak systolic velocity and/or abnormal ductus venosus flow in the donor conveyed poorer prognosis. Although donor neonatal survival after laser surgery was lower for patients with stage III twin-twin transfusion syndrome with donor fetal growth restriction type IIb than patients with stage III twin-twin transfusion syndrome with donor fetal growth restriction with type IIa, laser surgery for fetal growth restriction type IIb in the setting of twin-twin transfusion syndrome (as opposed to pure selective fetal growth restriction type IIb) still allows for the possibility of dual survivorship and should be offered with shared decision-making when counseling patients on management options.

Consenso SOCHOG/SOCHUMB: utilizar en Chile la curva estándar OMS ultrasonográfica de crecimiento fetal / SOCHOG/SOCHUMB consensus: OMS fetal ultrasound curve is the standard curve for ultrasound growth assessment to use in Chile

La Sociedad Chilena de Obstetricia y Ginecología (SOCHOG) y la Sociedad Chilena de Ultrasonido en Medicina y Biología (SOCHUMB) convocaron a un comité de expertos en el tema de ultrasonido y crecimiento fetal con el fin de proponer utilizar la curva fetal que mejor se adapte a la población chilena. Luego de la discusión, al no contar con curvas chilenas de crecimiento fetal, se concluye proponer que la curva estándar de la Organización Mundial de la Salud (OMS) sería la indicada dada la calidad de su metodología y por ser multicéntrica.

The Chilean Society of Obstetrics and Gynecology (SOCHOG) and the Chilean Society of Ultrasound in Medicine and Biology (SOCHUMB) have convened a committee of experts on the subject of ultrasound and fetal growth in order to propose using the fetal curve that best adapts to the Chilean population. After the discussion, since there are no Chilean fetal growth curves, it is concluded that the World Health Organization (WHO) standard curve would be the one to use given the quality of its methodology and the fact that it is multicentric.

Maternal urinary bisphenols and phthalates in relation to estimated fetal weight across mid to late pregnancy.

BACKGROUND: Bisphenols and phthalates are high production volume chemicals used as additives in a variety of plastic consumer products leading to near ubiquitous human exposure. These chemicals have established endocrine disrupting properties and have been linked to a range of adverse reproductive and developmental outcomes. Here, we investigated exposure in relation to fetal growth. METHODS: Participants included 855 mother-fetal pairs enrolled in the population-based New York University Children's Health and Environment Study (NYU CHES). Bisphenols and phthalates were measured in maternal urine collected repeatedly during pregnancy. Analyses included 15 phthalate metabolites and 2 bisphenols that were detected in 50 % of participants or more. Fetal biometry data were extracted from electronic ultrasonography records and estimated fetal weight (EFW) was predicted for all fetuses at 20, 30, and 36 weeks gestation. We used quantile regression adjusted for covariates to model exposure-outcome relations across percentiles of fetal weight at each gestational timepoint. We examined sex differences using stratified models. RESULTS: Few statistically significant associations were observed across chemicals, gestational time periods, percentiles, and sexes. However, within gestational timepoints, we found that among females, the molar sums of the phthalates DiNP and DnOP were generally associated with decreases in EFW among smaller babies and increases in EFW among larger babies. Among males, the opposite trend was observed. However, confidence intervals were generally wide at the tails of the distribution. CONCLUSION: In this sample, exposure to bisphenols and phthalates was associated with small sex-specific shifts in fetal growth; however, few associations were observed at the median of fetal weight and confidence intervals in the tails were wide. Findings were strongest for DiNP and DnOP, which are increasingly used as replacements for DEHP, supporting the need for future research on these contaminants.

Effect of monosodium glutamate on fetal development and progesterone level in pregnant Wistar Albino rats.

Monosodium glutamate (MSG) is a widespread flavor enhancer and stabilizer in manufactured or packaged foods that possess myriad adverse effects. This study aimed to evaluate the effect of MSG on placental progesterone receptors and fetal development. Thirty pregnant Wistar Albino rats were divided into three groups (ten/each). The control group (G1) gavaged distilled water only, low-dose treated group (G2) gavaged 3 g/kg MSG, and high-dose treated group (G3) gavaged 6 g/kg MSG from 1st to 18th days of gestation, and all pregnant rats were sacrificed on the 19th day of gestation. The effect of MSG on fetal weights, crown vertebral length (CVL), placental weight, placental ghrelin expression, and fetal skeleton examination were estimated. MSG induced a significant decrease in fetal weights, CVL lengths, placental weight, and ghrelin expression in both treatment groups compared to the control group. Several parts of the fetal skeleton showed incomplete ossification and delayed chondrification in which high-dose maternally treated fetuses were more affected. Many degenerative changes were detected in both maternal and fetal liver and kidney tissues in MSG-treated groups. Moreover, MSG caused a significant increase in serum ALT, ALP, and creatinine levels in pregnant rats' blood. Serum progesterone was only elevated in G3 on the 19th day of gestation. This study showed that the administration of MSG during pregnancy adversely influences fetal growth and skeletal development and caused several biochemical and histological changes in the maternal and fetal liver and kidney tissues which assure the toxic and teratogenic effects of MSG.