Prenatal glucocorticoids exposure and adverse cardiovascular effects in offspring.

Glucocorticoids (GCs) are steroid hormones fundamental to the body's normal physiological functions and are pivotal in fetal growth and development. During gestation, the mother's cortisol concentration (active GCs) escalates to accommodate the requirements of fetal organ development and maturation. A natural placental GCs barrier, primarily facilitated by 11ß hydroxysteroid dehydrogenase 2, exists between the mother and fetus. This enzyme transforms biologically active cortisol into biologically inactive corticosterone, thereby mitigating fetal GCs exposure. However, during pregnancy, the mother may be vulnerable to adverse factor exposures such as stress, hypoxia, caffeine, and synthetic GCs use. In these instances, maternal serum GCs levels may surge beyond the protective capacity of the placental GCs barrier. Moreover, these adverse factors could directly compromise the placental GCs barrier, resulting in excessive fetal exposure to GCs. It is well-documented that prenatal GCs exposure can detrimentally impact the offspring's cardiovascular system, particularly in relation to blood pressure, vascular function, and heart function. In this review, we succinctly delineate the alterations in GCs levels during pregnancy and the potential mechanisms driving these changes, and also analyze the possible causes of prenatal GCs exposure. Furthermore, we summarize the current advancements in understanding the adverse effects and mechanisms of prenatal GCs exposure on the offspring's cardiovascular system.

Maternal exposure to ambient particulate matter on the growth of twin fetuses after in vitro fertilization.

BACKGROUND: While ambient air pollution has been associated with fetal growth in singletons, its correlation among twins is not well-established due to limited research in this area. METHODS: The effects of exposure to PM2.5 particulate matter and its main components during pregnancy on birth weight and the incidence of large for gestational age (LGA) were investigated in 6177 twins born after in vitro fertilization at the Center for Reproductive Medicine of Shanghai Ninth People's Hospital (Shanghai, China) between 2007 and 2021. Other birth weight-related outcomes included macrosomia, low birth weight, very low birth weight, and small for gestational age (SGA). The associations of PM2.5 exposure with birth weight outcomes were analyzed using linear mixed-effect models and random-effect logistic regression models. Distributed lag models were incorporated to estimate the time-varying associations. RESULTS: The findings revealed that an interquartile range (IQR) increase (18 µg/m3) in PM2.5 exposure over the entire pregnancy was associated with a significant increase (57.06 g, 95 % confidence interval [CI]: 30.91, 83.22) in the total birth weight of twins. The effect was more pronounced in larger fetuses (34.93 g, 95 % CI: 21.13, 48.72) compared to smaller fetuses (21.77 g, 95 % CI: 6.94, 36.60) within twin pregnancies. Additionally, an IQR increase in PM2.5 exposure over the entire pregnancy was associated with a 34 % increase in the risk of LGA (95 % CI: 11 %, 63 %). Furthermore, specific chemical components of PM2.5, such as sulfate (SO42-), exhibited effect estimates comparable to the PM2.5 total mass. CONCLUSION: Overall, the findings indicate that exposures to PM2.5 and its specific components are associated with fetal overgrowth in twins.

Fetal and obstetrics manifestations of mitochondrial diseases.

During embryonic and neonatal development, mitochondria have essential effects on metabolic and energetic regulation, shaping cell fate decisions and leading to significant short- and long-term effects on embryonic and offspring health. Therefore, perturbation on mitochondrial function can have a pathological effect on pregnancy. Several shreds of evidence collected in preclinical models revealed that severe mitochondrial dysfunction is incompatible with life or leads to critical developmental defects, highlighting the importance of correct mitochondrial function during embryo-fetal development. The mechanism impairing the correct development is unknown and may include a dysfunctional metabolic switch in differentiating cells due to decreased ATP production or altered apoptotic signalling. Given the central role of mitochondria in embryonic and fetal development, the mitochondrial dysfunction typical of Mitochondrial Diseases (MDs) should, in principle, be detectable during pregnancy. However, little is known about the clinical manifestations of MDs in embryonic and fetal development. In this manuscript, we review preclinical and clinical evidence suggesting that MDs may affect fetal development and highlight the fetal and maternal outcomes that may provide a wake-up call for targeted genetic diagnosis.

Histomorphometric and developmental analysis of human fetal caecum and appendix with its embryological significance.

PURPOSE: The variable positions of the appendix can mislead surgeons and physicians to a wrong diagnosis. When appendicitis happens in subhepatic caecum, it can be misdiagnosed and can lead to severe complications during surgical procedures. Therefore, this study aimed to understand the histomorphometric development of the appendix and caecum and to identify when lymphoid follicles appear in the appendix during fetal life. METHODS: The study was conducted on a total of 50 fetuses. The caecum and appendix were carefully dissected. Their position and various measurements were observed. Afterwards, the appendix was taken out for histological processing. All three layers, mucosa, submucosa, and muscularis externa were measured using Image Analyzer Software Image Pro Premiere 9.1, and the appearance of lymphoid follicles was also examined. Results were analyzed using SPSS statistical software. RESULTS: During the 1st, 2nd, and 3rd trimesters the most common caecum type was type 1: as a lengthy tube, type 3: The lateral wall expanded more, thus it has an asymmetric saccule, and type 4: adult-like caecum. The caecum was mostly situated in the right lumbar region in the 2nd and 3rd trimesters. In the 1st trimester, it was subhepatic in position. The most common position of the appendix was 11 o'clock in 1st and 3rd trimesters. 2nd trimester's most common position of the appendix was 12 o'clock. The thickness of the mucosa, submucosa, and the muscularis externa increases as the trimester increases. The lymphoid follicles have appeared during the 2nd trimester. CONCLUSION: The knowledge from this study will be useful in the diagnosis and treatment of malformations, pathology, and anomalies of the caecum and appendix due to congenital causes.

Predicting newborn birth outcomes with prenatal maternal health features and correlates in the United States: a machine learning approach using archival data.

BACKGROUND: Newborns are shaped by prenatal maternal experiences. These include a pregnant person's physical health, prior pregnancy experiences, emotion regulation, and socially determined health markers. We used a series of machine learning models to predict markers of fetal growth and development-specifically, newborn birthweight and head circumference (HC). METHODS: We used a pre-registered archival data analytic approach. These data consisted of maternal and newborn characteristics of 594 maternal-infant dyads in the western U.S. Participants also completed a measure of emotion dysregulation. In total, there were 22 predictors of newborn HC and birthweight. We used regularized regression for predictor selection and linear prediction, followed by nonlinear models if linear models were overfit. RESULTS: HC was predicted best with a linear model (ridge regression). Newborn sex (male), number of living children, and maternal BMI predicted a larger HC, whereas maternal preeclampsia, number of prior preterm births, and race/ethnicity (Latina) predicted a smaller HC. Birthweight was predicted best with a nonlinear model (support vector machine). Occupational prestige (a marker similar to socioeconomic status) predicted higher birthweight, maternal race/ethnicity (non-White and non-Latina) predicted lower birthweight, and the number of living children, prior preterm births, and difficulty with emotional clarity had nonlinear effects. CONCLUSIONS: HC and birthweight were predicted by a variety of variables associated with prenatal stressful experiences, spanning medical, psychological, and social markers of health and stress. These findings may highlight the importance of viewing prenatal maternal health across multiple dimensions. Findings also suggest that assessing difficulties with emotional clarity during standard obstetric care (in the U.S.) may help identify risk for adverse newborn outcomes.

Investigating the IGF axis as a pathway for intergenerational effects.

Early nutritional and growth experiences can impact development, metabolic function, and reproductive outcomes in adulthood, influencing health trajectories in the next generation. The insulin-like growth factor (IGF) axis regulates growth, metabolism, and energetic investment, but whether it plays a role in the pathway linking maternal experience with offspring prenatal development is unclear. To test this, we investigated patterns of maternal developmental weight gain (a proxy of early nutrition), young adult energy stores, age, and parity as predictors of biomarkers of the pregnancy IGF axis (n = 36) using data from the Cebu Longitudinal Health and Nutrition Survey in Metro Cebu, Philippines. We analyzed maternal conditional weight measures at 2, 8, and 22 years of age and leptin at age 22 (a marker of body fat/energy stores) in relation to free IGF-1 and IGFBP-3 in mid/late pregnancy (mean age = 27). Maternal IGF axis measures were also assessed as predictors of offspring fetal growth. Maternal age, parity, and age 22 leptin were associated with pregnancy free IGF-1, offspring birth weight, and offspring skinfold thickness. We find that free IGF-1 levels in pregnancy are more closely related to nutritional status in early adulthood than to preadult developmental nutrition and demonstrate significant effects of young adult leptin on offspring fetal fat mass deposition. We suggest that the previously documented finding that maternal developmental nutrition predicts offspring birth size likely operates through pathways other than the maternal IGF axis, which reflects more recent energy status.

Nutraceuticals in Pregnancy: A Special Focus on Probiotics.

The placenta is crucial to fetal development and performs vital functions such as nutrient exchange, waste removal and hormone regulation. Abnormal placental development can lead to conditions such as fetal growth restriction, pre-eclampsia and stillbirth, affecting both immediate and long-term fetal health. Placental development is a highly complex process involving interactions between maternal and fetal components, imprinted genes, signaling pathways, mitochondria, fetal sexomes and environmental factors such as diet, supplementation and exercise. Probiotics have been shown to make a significant contribution to prenatal health, placental health and fetal development, with associations with reduced risk of preterm birth and pre-eclampsia, as well as improvements in maternal health through effects on gut microbiota, lipid metabolism, vaginal infections, gestational diabetes, allergic diseases and inflammation. This review summarizes key studies on the influence of dietary supplementation on placental development, with a focus on the role of probiotics in prenatal health and fetal development.

Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism.

BACKGROUND: The growth factor receptor bound protein 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles for Grb10 and Grb14 in glucose-regulated energy homeostasis. Both Grb10 KO and Grb14 KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition, Grb10 strongly inhibits fetal growth such that at birth Grb10 KO mice are 30% larger by weight than wild type littermates. RESULTS: Here, we generate a Grb7 KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this, Grb7 and Grb14 did not have a major role in influencing fetal growth, either alone or in combination with Grb10. At birth, in most respects both Grb7 KO and Grb14 KO single mutants were indistinguishable from wild type, while Grb7:Grb10 double knockout (DKO) were near identical to Grb10 KO single mutants and Grb10:Grb14 DKO mutants were slightly smaller than Grb10 KO single mutants. In the developing kidney Grb7 had a subtle positive influence on growth. An initial characterisation of Grb7 KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having a significantly smaller renal white adipose tissue depot and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller white adipose depots, without improved glucose clearance. CONCLUSIONS: Grb7 and Grb14 do not have significant roles as inhibitors of fetal growth, unlike Grb10, and instead Grb7 may promote growth of the developing kidney. In adulthood, Grb7 contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.

The characterization of developmental toxicity in fetal offspring induced by acetaminophen exposure during pregnancy.

OBJECTIVE: Acetaminophen (APAP), an antipyretic and analgesic commonly used during pregnancy, has been recognized as a novel environmental contaminant. Preliminary evidence suggests that prenatal acetaminophen exposure (PAcE) could adversely affect offspring's gonadal and neurologic development, but there is no systematic investigation on the characteristics of APAP's fetal developmental toxicity. METHODS: Pregnant mice were treated with 100 or 400 mg/kg∙d APAP in the second-trimester, or 400 mg/kg∙d APAP in the second- or third-trimester, or different courses (single or multiple) of APAP, based on clinical regimen. The effects of PAcE on pregnancy outcomes, maternal/fetal blood phenotypes, and multi-organ morphological and functional development of fetal mice were analyzed. RESULTS: PAcE increased the incidence of adverse pregnancy outcomes and altered blood phenotypes including aminotransferases, lipids, and sex hormones in dams and fetuses. The expression of key functional genes in fetal organs indicated that PAcE inhibited hippocampal synaptic development, sex hormone synthesis, and osteogenic and chondrogenic development, but enhanced hepatic lipid synthesis and uptake, renal inflammatory hyperplasia, and adrenal steroid hormone synthesis. PAcE also induced marked pathological alterations in the fetal hippocampus, bone, kidney, and cartilage. The sensitivity rankings of fetal organs to PAcE might be hippocampus/bone > kidney > cartilage > liver > gonad > adrenal gland. Notably, PAcE-induced multi-organ developmental toxicity was more considerable under high-dose, second-trimester, and multi-course exposure and in male fetuses. CONCLUSION: This study confirmed PAcE-induced alterations in multi-organ development and function in fetal mice and elucidated its characteristics, which deepens the comprehensive understanding of APAP's developmental toxicity.

The impact of Ramadan fasting on oxidative stress levels in the second trimester of pregnancy.

BACKGROUND: The primary objective of this study was to assess the effect of fasting during Ramadan on maternal oxidative stress levels and foetal development; pregnant women with uncomplicated, singleton pregnancies in the second trimester. METHODS: During the month of Ramadan, 23 March 2023 to 20 April 2023, 50 fasting and 50 non-fasting healthy pregnant women were enrolled in this prospective study. The fasting hours were about 14 h per day in that season. Pregnant women in the second trimester were enrolled in the study. Total antioxidant status (TAS), total oxidant status (TOS) and the oxidative stress index (OSI) were measured from maternal serum samples taken on a fasting day at the end of Ramadan. To evaluate the impact of Ramadan on the foetus, Doppler ultrasonography was performed in the beginning and then at the end of Ramadan in all participants and was used for the following measurements: Increase of biparietal diameter, femur length, estimated foetal body weight, amniotic fluid index and umbilical artery systolic/diastolic ratio. To discern differences between distinct cohorts, independent t-tests and Mann-Whitney's U-tests were employed based on the data distribution. A p value threshold of less than .05 was established to determine statistical significance. RESULTS: TAS level was found to be significantly lower in the group that fasted for more than 15 days compared to the non-fasting group that did not fast (p = .003), but no significant differences were found between the groups in terms of TOS and OSI (p < .05). Obstetric ultrasound parameters showed no significant differences between the two groups (p < .05). CONCLUSIONS: The present study suggests that fasting during the second trimester of pregnancy does not substantially impact maternal or foetal health, as indicated by most oxidative stress markers and foetal parameters studied. However, the observed reduction in the TAS levels in the fasting group warrants further investigation.

Ramadan is the holy month for the Islamic World. During Ramadan, a pregnant woman is exempt from fasting if she believes that fasting would endanger her own health or that of the foetus.The significance of oxidative stress in pregnancy is widely recognised as it is thought to play a role in conditions such as preeclampsia, gestational diabetes and preterm labour. However, the effect of fasting during Ramadan on maternal oxidative stress and foetal development remains unclear.During Ramadan, no adverse foetal effects were observed in fasting pregnant women compared to non-fasting pregnant women. The total antioxidant status (TAS) levels were significantly reduced in the fasting group, suggesting an adaptive metabolic response or influence of fasting duration. Lower TAS levels may not only be attributed to fasting during Ramadan but also to changes in dietary habits and lifestyle factors (e.g. physical activity and sleep).

Evaluation of Polyphenol Intake in Pregnant Women from South-Eastern Spain and the Effect on Anthropometric Measures at Birth and Gestational Age.

During pregnancy, controlling nutrition is crucial for the health of both mother and foetus. While polyphenols have positive health effects, some studies show harmful outcomes during pregnancy. This study evaluated polyphenol intake in a cohort of mother-child pairs and examined its effects on foetal anthropometric parameters. Polyphenol intake was assessed using food frequency questionnaires (FFQs) and 24-h dietary recalls, and analysed with the Phenol-Explorer database. Gestational age and birth measurements were retrieved from medical records. Statistical analyses validated dietary records and assessed polyphenol impact using multivariate generalised linear models. The study found that mean gestational age was 39.6 weeks, with a mean birth weight of 3.33 kg. Mean total polyphenol intake by FFQ was 2231 mg/day, slightly higher than 24-h recall data. Flavonoids and phenolic acids constituted 52% and 37% of intake, respectively, with fruits and legumes as primary sources. This study highlights the use of FFQs to estimate polyphenol intake. Furthermore, the study found associations between polyphenol consumption and anthropometric parameters at birth, with the effects varying depending on the type of polyphenol. However, a more precise evaluation of individual polyphenol intake is necessary to determine whether the effects they produce during pregnancy may be harmful or beneficial for foetal growth.

Impact of Ionizing Radiation Exposure on Placental Function and Implications for Fetal Programming.

Accidental exposure to high-dose radiation while pregnant has shown significant negative effects on the developing fetus. One fetal organ which has been studied is the placenta. The placenta performs all essential functions for fetal development, including nutrition, respiration, waste excretion, endocrine communication, and immunological functions. Improper placental development can lead to complications during pregnancy, as well as the occurrence of intrauterine growth-restricted (IUGR) offspring. IUGR is one of the leading indicators of fetal programming, classified as an improper uterine environment leading to the predisposition of diseases within the offspring. With numerous studies examining fetal programming, there remains a significant gap in understanding the placenta's role in irradiation-induced fetal programming. This review aims to synthesize current knowledge on how irradiation affects placental function to guide future research directions. This review provides a comprehensive overview of placental biology, including its development, structure, and function, and summarizes the placenta's role in fetal programming, with a focus on the impact of radiation on placental biology. Taken together, this review demonstrates that fetal radiation exposure causes placental degradation and immune function dysregulation. Given the placenta's crucial role in fetal development, understanding its impact on irradiation-induced IUGR is essential.

Fetal Growth Following Electronic Cigarette Use in Pregnancy.

Electronic cigarette (e-cig) use in pregnancy is common, but potential effects on fetal development are largely unknown. This study's goal was to examine the association between e-cig exposure and fetal growth. Data were extracted from medical charts in this single-site retrospective study. The sample, excluding those with known tobacco, alcohol, illicit drug, opioid, and benzodiazepine use, contained women who used e-cigs throughout pregnancy and non-e-cig user controls. Fetal size measurements from second- and third-trimester ultrasounds and at birth were expressed as percentiles for gestational age. Following adjustment for confounding factors, in the second trimester, only femur length was significant, with an adjusted deficit of 11.5 percentile points for e-cig exposure compared to controls. By the third trimester, the femur length difference was 28.5 points, with the fetal weight difference also significant (17.2 points). At birth, all three size parameter differences between groups were significant. Significant size deficits were predicted by prenatal e-cig exposure, becoming larger and impacting more parameters with increasing gestation. While additional studies are warranted to confirm and expand upon these findings, this study adds to emerging data pointing to specific harms following e-cig exposure in pregnancy and suggests that e-cigs may not be a "safer" alternative to combustible cigarette smoking in pregnancy.

Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.

Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.

Evaluation of levamlodipine benzenesulfonate compound I for embryo-fetal developmental toxicity in SD rats and genotoxicity.

In the present study, the effects of levamlodipine benzenesulfonate on the development of fertile Sprague-Dawley (SD) rats, their embryos, and littermates were assessed using an embryo-fetal developmental toxicity test. Maternal body weight reduction was observed at a dose of 20 mg/kg, but it recovered after treatment cessation. The 20 mg/kg dose group showed a skewed sex ratio in fetal rats, with a higher proportion of males. While some effects on fetal sternum development were observed at 20 mg/kg, no skeletal malformations were observed. No significant gross morphological abnormalities were detected in the dams (mothers), no significant embryotoxicity or foetotoxicity in fetal rats and no significant effects on fetal length and weight development at doses of 5 and 10 mg/kg. Genotoxicity was evaluated using a combination of the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration assay, and the ICR mouse bone marrow micronucleus test. The Ames test results indicated substantial bacteriostatic effects at doses of 500 and 5000 mg/dish, with no mutagenicity observed at doses of 0.5, 5, and 50 mg/dish. No significant effect on the aberration rate of CHO cell chromosomes was found at doses of 2.8, 5.6, and 11.2 mg/mL. In the ICR mouse micronucleus test, no micronucleus-inducing effect was observed at doses of 3.125, 6.25, and 12.5 mg/kg in each treatment group. In conclusion, under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for developmental toxicity of levamlodipine benzenesulfonate in fertile SD rats, their embryos, and littermates was established to be 10 mg/kg/day. Levamlodipine benzenesulfonate did not exhibit significant genotoxicity.

REPRODUCTIVE AGEING: BGP-15 mitigates adverse impacts of aging on sperm quality, fertility, and offspring health in male mice.

In Brief: Aging in men is associated with diminished sperm quality and a higher incidence of altered fetal development and miscarriage in resultant pregnancies. This study in mice identifies a therapeutic compound that, when administered to aged males, improves sperm quality, subsequent embryo development and post-natal offspring health. Abstract: Aging in men is associated with diminished sperm quality and a higher incidence of altered fetal development and miscarriage in resultant pregnancies. We used a mouse model of advanced paternal age to characterize embryonic development in older male mice and tested whether pre-conception treatment with the mitochondrial activator BGP-15 improves reproductive outcomes in old males. Like older men, reproductively old male mice had higher levels of sperm DNA damage and delayed pre-implantation development, associated with a reduced fetal weight and placental weight. Analysis of neonatal outcomes of in vivo-conceived offspring found that pups sired by old males were smaller, had delayed locomotor development, and increased mortality. BGP-15 treatment for 5 days prior to conception reduced sperm DNA oxidation levels and improved on-time embryo development after IVF and pup survival. BGP-15 treatment for 3 weeks prior to conception improved on-time pre-implantation embryo development and fetal viability and increased fetal size in pregnancies sired by old males. These results validate that ageing negatively affects male fertility and offspring physiology and indicates that pre-conception treatment with BGP-15 has the potential to improve sperm quality as well as early embryo development and post-natal health.

New approach methodologies to confirm developmental toxicity of pharmaceuticals based on weight of evidence.

The aim of embryo-fetal developmental toxicity assessments for pharmaceuticals is to inform potential risk of adverse pregnancy outcome, which has traditionally relied on studies in pregnant animals. Recent updates to international safety guidelines (ICH S5R3) have incorporated information on how to use weight of evidence and alternative assays to reduce animal use while still informing risk of fetal harm. Uptake of these alternative approaches has been slow due to limitations in understanding how alternative assays translate to in vivo effects and then relevance to human exposure. To understand the predictivity of new approach methodologies for developmental toxicity (DevTox NAMs), we used two pharmaceutical examples (glasdegib and lorlatinib) to illustrate the value of DevTox NAMs to complement weight of evidence (WoE) assessments while considering the relationship of concentration-effect levels in NAMs to in vivo studies. The in vitro results generated in a battery of assays (mEST, rWEC, zebrafish, and human based stem cells) confirmed the WoE based on literature and further confirmed by preliminary embryo-fetal development data. The data generated for these two compounds supports integrating DevTox NAMs into the developmental toxicity assessment for advanced cancer indications.

A customised fetal growth and birthweight standard for Qatar: a population-based cohort study.

OBJECTIVES: Customized birthweight centiles have improved the detection of small for gestational age (SGA) and large for gestational age (LGA) babies compared to existing population standards. This study used perinatal registry data to derive coefficients for developing customized growth charts for Qatar. METHODS: The PEARL registry data on women delivering in Qatar (2017-2018) was used to develop a multivariable linear regression model predicting optimal birthweight. Physiological variables included gestational age, maternal height, weight, ethnicity, parity, and sex of the baby. Pathological variables such as hypertension, preexisting and gestational diabetes and smoking were calculated and excluded to derive the optimal weight at term. RESULTS: The regression model found a term optimal birthweight of 3,235 g for a Qatari nationality mother with median height (159 cm), booking weight (72 kg), parity (1) and gestation at birth (276 days) at the end of an uncomplicated pregnancy. Constitutional coefficients significantly affecting birthweight were gestational age, height, weight, and parity. The main pathological factors were preexisting diabetes (increase by +175.7 g) and smoking (decrease by -190.9 g). The SGA and LGA rates in the entire cohort after applying the population-specific customized centiles were 11.1 and 12.2 %, respectively (contrasting with the Hadlock standard: SGA-26.3 % and LGA-1.8 %, and Fenton standard: SGA-12.9 % and LGA-4.0 %). CONCLUSIONS: Constitutional and pathological variations in fetal growth and birthweight apply in the maternity population in Qatar and have been quantified to allow the generation of customised charts for better identification of pregnancies with abnormal growth. Currently in-use population standards may misdiagnose many SGA and LGA babies.

Gestational diabetes mellitus management according to ultrasound fetal growth versus strict glycemic treatment in singleton pregnancies: A systematic review and meta-analysis of clinical trials.

AIM: The objective of this meta-analysis was to evaluate obstetric outcomes in gestational diabetes mellitus (GDM) patients treated with flexible management based on intrauterine ultrasound fetal growth (FMIUFG) or strict maternal glycemic adjustment (SMGA). METHODS: We performed a comprehensive systematic review of electronic databases for randomized clinical trials (RCTs) comparing obstetrics outcomes of singleton GDM patients managed according to FMIUFG or SMGA. The review protocol was registered in PROSPERO (CRD497888). Searches were conducted in PubMed, Embase, Cochrane, and LILACS. Primary outcomes were gestational age at delivery and birth weight. Random-effect model meta-analyses were used to minimize the effects of uncertainty associated with inter-study variability. Results are reported as standardized mean differences (SMDs) or as odds ratios (ORs) and their 95% confidence interval (CI). Heterogeneity between studies was estimated using the I2 statistic. The Cochrane Risk of Bias Scale was used to assess the quality of studies. There were five RCTs with low to moderate risk of bias, including 450 patients managed according to the FMIUFSG and 381 according to the SMGA. RESULTS: The macrosomia (birthweight >4000 g) rate was lower in pregnancies managed according to FMIUFG than SMGA adjustments (OR: 0.34; 95%CI: 0.16, 0.71). There were no significant differences in hypertensive disorder, cesarean section, neonatal intensive care unit admission, and large newborn for gestational age rates. CONCLUSIONS: The macrosomia rate was lower in women managed with the FMIUFG. There were no significant differences in other obstetric and neonate outcomes.