Fetal Sex Research Articles

Non-genetic risk factors for preeclampsia: an updated umbrella review

Abstract Background Preeclampsia (PE) is a common pregnancy disorder with complex mechanisms, and multiple risk factors may contribute to its development. Our objective is to update our literature search from our previous umbrella review, summarizing recent evidence on non-genetic risk factors associated with PE and assessing their credibility to identify those supported by robust epidemiological evidence. Methods We searched PubMed, EMBASE, Scopus, and ISI Web of Science up to June 2023. For each meta-analysis, we computed summary effect estimates, 95% confidence intervals, 95% prediction intervals, and assessed heterogeneity using I², while also examining small-study effects and excess significance bias. Quality assessment was conducted using the AMSTAR-2 tool. Results 89 meta-analyses were identified, providing data on 219 associations. Of these, 151 (69%) showed statistically significant findings at P < 0.05, with 52 (24%) remaining significant at P < 10-6. Large or very large heterogeneity was observed in 121 (55%) associations. Evidence for small-study effects and excess significance bias was found in 27 (12%) and 29 (13%) associations, respectively. Only 16 (7%) presented convincing evidence: Polycystic Ovary Syndrome (PCOS), PCOS (adjusted), Obstructive Sleep Apnea (OSA), Obesity (adjusted), Chronic Kidney Disease (CKD), Pregnancy Intrahepatic Cholestasis, SARS-CoV-2 infection (adjusted), Oocyte donation (OD) vs. In vitro fertilization (IVF), Fresh embryo transfer vs. spontaneous conception (SC) (singleton), Frozen embryo transfer vs. SC, OD vs. SC (singleton), IVF-OD vs. IVF-AO, IVF-OD fresh ET vs. IVF-AO fresh ET, NC frozen embryo transfer vs. AC frozen embryo transfer, Fetal sex (term), and Smoking. Conclusions Maternal health conditions like PCOS, along with reproductive interventions such as OD and IVF, as well as lifestyle factors like obesity and smoking, showed convincing associations with PE. Key messages • Maternal health conditions, reproductive interventions, and lifestyle factors showed compelling evidence of association with preeclampsia. • Our findings emphasize the multifactorial nature of preeclampsia and suggest potential avenues for further research and clinical intervention.

Phosphodiesterase Inhibitors in Fetal Growth Restriction: Do Not Forget to Consider Fetal Sex and Subcellular Compartmentation.

Fetal growth restriction (FGR) is a common complication of pregnancy, associated with major perinatal mortality and morbidity, and with an increased risk to develop cardiometabolic diseases later in life. There is currently no effective approach to prevent or treat FGR, despite numerous animal and human studies assessing substances likely to improve fetal growth. Phosphodiesterase (PDE) inhibitors appeared as promising drugs to improve FGR management. However, to date, studies have led to somewhat disappointing or controversial results. In this Opinion article, we would like to draw attention to the need to consider the biological sex and the relative reactivity of human umbilical vein and arteries when developing therapeutic interventions to improve human umbilical circulation using PDE inhibitors. Indeed, we suspect that fetal sex, vessel type and the presence of FGR may influence subcellular compartmentation, which could jeopardize beneficial effects of PDE inhibitors.

Prediction of Fetal Death in Preterm Preeclampsia Using Fetal Sex, Placental Growth Factor and Gestational Age.

Preeclampsia (PE) is a systemic disease that affects 4.6% of pregnancies. Despite the existence of a first-trimester screening for the prediction of preterm PE, no consensus exists regarding neither the right moment to end the pregnancy nor the appropriate variables to estimate the prognosis. The objective of this study was to obtain a prediction model for perinatal death in patients with preterm PE, useful for clinical practice. Singleton pregnant women with PE and preterm delivery were included in an observational retrospective study. Multiple maternal and fetal variables were collected, and several multivariable logistic regression analyses were applied to construct models to predict perinatal death, selecting the most accurate and reproducible according to the highest area under the curve (AUC) and the lowest Akaike Information Criteria (AIC). A group of 148 pregnant women were included, and 18 perinatal deaths were registered. Univariable logistic regression selected as statistically significant variables the following: gestational age (GA) at admission, fetal sex, poor response to antihypertensive drugs, PlGF, umbilical artery (UA) pulsatility index (PI), cerebroplacental ratio (CPR), and absent/reversed ductus venosus (DV). The multivariable model, including all these parameters, presented an AUC of 0.95 and an AIC of 76.5. However, a model including only GA and fetal sex presented a similar accuracy with the highest simplicity (AUC 0.93, AIC 67.6). Finally, in fetuses with a similar GA, fetal death became dependent on PlGF and fetal sex, underlying the role of fetal sex in all circumstances. Female fetal sex and low PlGF are notorious predictors of perinatal death in preterm PE, only surpassed by early GA at birth.

B-218 Inconclusive results in the Fetal Sex Determination from maternal plasma assay may indicate miscarriage

Abstract Background The purpose of this study was to evaluate the miscarriage rates from patients presenting inconclusive results in a cell-free DNA fetal sex determination test at Dasa, a Brazilian laboratory, between 2021 and 2023. Methods In validating the fetal sex determination test, a Ct value range was established to assign the presence of the Y chromosome on maternal plasma and a gray zone for determining an inconclusive result. In this case, our operational procedure is to repeat the analysis from the beginning, due to plasma volume limitation. When the result remains inconclusive upon repetition a new sample is requested.After the 2nd sample collection with inconclusive results, cases are forwarded to specialized medical contact, when patient is informed and potential explanations for the rare situation of a repeat-indeterminate sex determination result are discussed.At the end of 2022, the need to widen the sex-determining range and consequently the inconclusive zone was routinely perceived. The main reason for this change was to reduce unnecessary repetitions. Results The adjustments of range reduced unnecessary repetition, requests for new samples and medical contacts (Table). Between 2021 and 2023 the median gestational age at 1st collect of medical contact was 9 weeks, and in cases of miscarriages was 10 (2022) and 8 weeks (2023). Conclusions The widening of the Y chromosome Ct range proved to be efficient on a routine basis without changing the result error rates, which since 2021 have remained at 0.05%. In addition to providing more precision to the assay, the newly established gray zone increased the positive predictive value for miscarriage. Our results, show that what was thought to be a limitation of the technique in determining the fetal sex may in fact, in many cases, be associated to fetal loss

Testing secondary sex ratio bias hypotheses in white-tailed deer in Mississippi, USA.

Natural selection favors individuals with the highest inclusive fitness (i.e., total number of descendants). In cases where one sex is more productive, one or both parents may maximize their inclusive fitness by investing in the offspring of the more prolific sex. Such preferential production can lead to skewed sex ratios at various life history stages, including at birth, resulting in secondary sex ratio bias. Several competing hypotheses have been proposed to explain observed variation in secondary sex ratios including Fisher's frequency dependence and two hypotheses related to maternal condition: Trivers-Willard and the local resource hypotheses. Although it has been shown that maternal condition can influence the number of offspring produced in white-tailed deer, there is no consensus as to which of the hypotheses drives sex ratio bias in wild populations. Using a spatiotemporally extensive dataset of pregnant white-tailed deer from Mississippi, USA, we examined fetal sex ratio in relation to the Fisherian frequency-dependence hypothesis and hypotheses related to maternal condition. While there was a male-sex ratio bias in pregnant females that reduced in intensity with the number of offspring, there was no support for condition-related hypotheses. Instead, secondary sex ratios for white-tailed deer in Mississippi were nearly consistent with Fisherian frequency dependence. Our findings add to the body of literature on secondary sex biases in white-tailed deer and help inform sex bias ratios for a southern population of a cervid of management importance in the US.

Maternal high BMI: Sex-dimorphic alterations in maternal and offspring stress indices

Maternal body mass index (BMI) influences pregnancy and birth outcomes along with child metabolic and neurodevelopmental health and fetal sex may be a moderating factor in these effects. Alternations in autonomic nervous system (ANS) functioning, identified in heart rate (HR) measurements, could present early markers of these prenatal programming effects in both the mother and the developing fetus. This study examines the associations between pre-pregnancy BMI and maternal and fetal ANS functioning and infant postnatal behavioral outcomes stratified by fetal sex. Pregnant women (N=176) were recruited at gestational week (GW) T1: 12–22 and categorized into Normal (BMI< 25) or High BMI (BMI > 25). Women attended laboratory sessions at T2: GW 23–28, and T3: GW 34–36 to assess maternal and fetal HR and HR variability (HRV) at baseline and after a stressor at T3. Infant behavior was assessed at 4 months using the Infant Behavior Questionnaire-Revised. Women with high BMI bearing female fetuses had higher HR and lower HRV at both gestational time points. Later in the third trimester, female fetuses of high BMI women exhibited lower HRV when challenged with a stressor. At 4 months, female infants were rated as having lower scores on the Orienting/Regulatory scale. Our findings provide evidence of female sex-specific programming of maternal pre-pregnancy BMI on maternal ANS regulation and neurodevelopment identified in-utero and continuing into early infancy.

Gestational urinary concentrations of glyphosate and aminomethylphosphonic acid in relation to preterm birth: the MIREC study.

Few high-quality studies have evaluated associations between urinary glyphosate or its environmental degradate (aminomethylphosphonic acid (AMPA)] and preterm birth (PTB). To quantify associations between urinary glyphosate and AMPA and preterm birth in the pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study and determine if associations differ by fetal sex. We measured first trimester urinary glyphosate and AMPA concentrations in MIREC participants who were recruited between 2008-2011 from 10 Canadian cities. Of the 1880 participants whose first trimester urine samples were analyzed for glyphosate or AMPA, 1765 delivered a singleton, live birth. Our primary outcome was preterm birth (PTB) defined as births occurring between 20 and <37 weeks. Secondary outcomes were spontaneous preterm births (sPTB) and gestational age. We modelled the hazard of PTB and sPTB using discrete time survival analysis with multivariable logistic regression to calculate odds ratios (OR). We used multivariable linear regression models to quantify associations between analytes and gestational age. To assess effect modification by fetal sex, we stratified all models and calculated interaction terms. In the logistic regressions models we additionally calculated the relative excess risk due to interaction. Six percent (n = 106) of the study population delivered preterm, and 4.7% (n = 83) had a spontaneous preterm birth. Median specific-gravity standardized concentrations of glyphosate and AMPA were 0.25 and 0.21 µg/L. Associations between both glyphosate or AMPA and PTB, sPTB, and gestational age centered around the null value. The adjusted ORs of PTB for each doubling of glyphosate and AMPA concentrations were 0.98 (95% CI: 0.94, 1.03) and 0.99 (95% CI: 0.92, 1.06) respectively. We observed no evidence of differences by fetal sex. In this Canadian pregnancy cohort, neither glyphosate nor AMPA urinary concentrations was associated with PTB or reduced gestational length.

PSV-13 Betaine supplementation and nutrient restriction during gestation: Influences on growth in fetal sheep offspring

Abstract Restricted nutrition during gestation can reduce offspring productivity. Supplementation of betaine, a methyl donor, promotes fetal growth and liver function. We hypothesized that nutrient restriction during gestation impairs growth, including organ weights and muscle mass, while betaine supplementation would alleviate these negative effects. To determine if maternal betaine supplementation during gestation would improve growth of offspring of restricted-fed dams, multiparous Dorset ewes (n = 47) were estrus synchronized and bred to one of three rams. Ewes confirmed pregnant with twins (n = 32) and singletons (n = 15) were randomly assigned to one of four diets [100% NRC requirements (CON), 60% NRC (RES), CON+betaine (CON+BET; 2 g/d), and RES+BET] from d 30 to 130 of gestation. Among the twins, there were 27 males (CON-8, RES-5, CON+BET-5, and RES+BET-9) and 37 females (CON-8, RES-9, CON+BET-11, and RES+BET-9). Within singletons, there were 7 males (CON-2, RES-2, CON+BET-2, and RES+BET-1) and 8 females (CON-3, RES-1, CON+BET-1, and RES+BET-3). Dam body weight (BW) was measured weekly from d 30 to d 130 of gestation, and diet adjusted accordingly. Dams were euthanized at d 130 of gestation and fetal BW and tissue weights were collected. Data were analyzed using RStudio with P ≤ 0.05 considered significant and 0.05 &amp;lt; P ≤ 0.10 as tendency. At d 130, dams carrying twin fetuses in the CON group were 11.3% and 19.1% heavier than RES and RES+BET dams, respectively (P ≤ 0.05), and CON+BET dams were 18.4% and 10.5% heavier than RES and BET+RES dams, respectively (P ≤ 0.07). However, dams with singletons showed no significant difference in BW (P ≥ 0.37). Regarding fetal BW for singletons, RES fetuses (3.80 ± 0.28kg) were lighter than CON (4.60 ± 0.21kg), CON+BET (4.72 ± 0.27kg), and RES+BET (4.59 ± 0.24kg; P ≤ 0.03). Whereas in twins, RES+BET fetuses (3.19 ± 0.11kg) were lighter than CON (3.68 ± 0.12kg), RES (3.73 ± 0.14kg), and CON+BET (3.60 ± 0.13kg; P ≤ 0.02). In all fetuses, the livers of male RES (28.0 ± 1.49g) and male RES+BET (27.7 ± 1.44g) tended to be heavier than those of female RES+BET (24.5 ± 1.19g; P ≤ 0.07). In terms of muscle mass, female CON+BET (9.33 ± 0.43g) fetuses tended to have greater longissimus muscle (LM) mass compared with female CON (8.30 ± 0.35; P = 0.06), whereas male RES (9.06 ± 0.44g) tended to have heavier LM than male CON+BET (8.02 ± 0.43g; P = 0.09). There were no observed effects of diet, fetal sex, or fetal number on the weights of heart, kidney, perirenal fat, pancreas, semitendinosus muscle, and triceps brachii muscle (P ≥ 0.11). These findings suggest that betaine supplementation may have a significant role in improving fetal BW in singleton pregnancies, with variable effects in twins. Additionally, betaine supplementation may have sex-specific effects on muscle development.

227 Moderate body weight loss reduces total antioxidant capacity in pregnant beef heifers and one-carbon metabolite supplementation does not mitigate this response

Abstract In beef heifers, body weight (BW) gain and physiological stress are important considerations for reproductive outcomes and whole herd production efficiencies. The objective of this study was to determine if dietary one-carbon metabolite (OCM) supplementation in moderate BW loss pregnant heifers alters circulating total antioxidant capacity, superoxide dismutase, and glutathione peroxidase activity. In a replicated 2 × 2 factorial, Angus-cross heifers (n = 81) were stratified by BW to gain 0.45 kg/d (CON) or lose 0.23 kg/d (RES) and receive corn carrier with OCM supplements (+OCM) or without (−OCM). The OCM supplements consisted of vitamin B12 (20 mg) and folate (320 mg) injections weekly and dietary rumen-protected methionine (7.4 g/d) and choline (44.4 g/d) from breeding (d 0) to d 63 of gestation. The four treatment groups were: CON−OCM (n = 20), CON+OCM (n = 21), RES−OCM (n = 21), and RES+OCM (n = 19). Heifers underwent estrus synchronization and were bred via artificial insemination using female sexed semen to a single sire. Pregnancy was diagnosed and fetal sex was verified on d 35 of gestation. Blood was collected and assayed for total antioxidant capacity, superoxide dismutase, and glutathione peroxidase activity on d −2 (baseline), 35, and 63 of gestation for all three replicates. Data were analyzed using the MIXED procedure of SAS with repeated measures to determine the effect of gain, supplement, day, and their two-way and three-way interactions. The gain × supplement interaction remained in all models, but other interactions were removed if P &amp;gt; 0.10. Replicate and heifer BW were included in the model as covariates and covariance structure was determined by lowest AIC and BIC. Statistical significance was considered at P ≤ 0.05 and tendencies at 0.05 &amp;lt; P ≤ 0.10. There was no BW gain × supplement interaction, or main effect of OCM supplements in total antioxidants. There was a gain × day effect (P ≤ 0.01), in which total antioxidants were increased on d 35 and further increased on d 63 in CON compared with RES treatments. There was no gain × supplement interaction, or main effect of gain or OCM supplements in superoxide dismutase and glutathione peroxidase. However, both superoxide dismutase and glutathione peroxidase were decreased (P ≤ 0.01) on d 63 compared with d 0 and 35. These data suggest that moderate BW loss reduces total antioxidant capacity in pregnant beef heifers, which could affect redox homeostasis. However, OCM supplements did not affect total antioxidant capacity, superoxide dismutase, or glutathione peroxidase. These findings are somewhat surprising considering oxidative stress has been well characterized in nutrient-restricted pregnancies, and given the interconnection between energy metabolism and one-carbon metabolism. Future research is warranted to fully elucidate the therapeutic effects of one-carbon metabolites.

The whole is lesser than the sum of its parts? Dissecting layer-enriched samples of rodent placenta is worth the effort

Gene expression in the placenta, assessed by bulk RNA-seq, is a common method to explore placental function. Many rodent studies homogenize the entire placenta, and yet doing so may obscure differences within specific functional regions such as the labyrinth, junctional zone and decidua. Conversely, analysis of the whole placenta could generate apparent differences due to changes in composition (e.g., relative amounts of labyrinth vs junctional zone) rather than differential gene expression. We assess the value of dissecting and separately analysing the labyrinth and junctional zone/decidua by comparing RNA-seq results from the labyrinth, junctional zone/decidua combined, and whole placenta from an experiment examining effects of maternal food restriction and fetal sex in C57BL6/J mice at gestational day 17.5. The number of genes identified as differentially expressed in response to maternal food restriction was substantially higher in the labyrinth (910 genes), than in the junctional zone/ decidua (50 genes), which in turn was slightly higher than in the whole placenta (3 genes). Only one gene was differentially expressed in all 3 tissue types, and 20 genes were differentially expressed in both the labyrinth and junctional zone/decidua. The larger number of differentially expressed genes in the labyrinth was due to both larger effect sizes and estimates of effect sizes having smaller standard errors. While dissection to obtain layer-enriched samples is slightly more time-consuming than collection of whole placenta and requires some practice, our results show that layer-enrichment is clearly worth the effort.

Ancestry and Fetal Sex Differences in Hofbauer Cell Gene Expression and Cell Communications in Mid-Gestation Human Placenta

Ancestry and Fetal Sex Differences in Hofbauer Cell Gene Expression and Cell Communications in Mid-Gestation Human Placenta

Placental ceramide content is decreased in maternal obesity and GDM, independent of fetal sex.

Placental ceramide content is decreased in maternal obesity and GDM, independent of fetal sex.

DNA concentrations in amniotic fluid according to gestational age and fetal sex: data from 2573 samples

PurposeIn some cases of prenatal genetic testing, an ample amount of fetal DNA is needed, to allow for parallel testing (conducting several genetic tests simultaneously). This study investigated the association between amniotic fluid DNA concentration and various factors. We aimed to define the required amount of amniotic fluid to be extracted in amniocentesis, to allow parallel testing throughout gestational weeks.MethodsDNA concentration was analyzed from amniocentesis samples taken during the years 2016–2022. Sex association was also analyzed in postnatal whole blood samples from a separate cohort. Theoretical minimum volume of amniotic fluid needed to ensure enough DNA for chromosomal microarray analysis and exome sequencing was calculated.ResultsWe focused our analysis on 2573 samples, which were taken during weeks 17–23 and 30–35. DNA concentrations increased from weeks 17 to 21, with relatively stable concentrations thereafter. Significantly higher DNA concentrations were seen in pregnancies of female fetuses. DNA concentrations in postnatal whole blood samples did not show this association. Across most weeks, the volume needed to extract 2 µg of DNA from 95% of the samples was about 34 ml.ConclusionDNA concentrations in amniotic fluid vary according to gestational age and are higher in pregnancies of female fetuses. This should be considered when determining the volume of fluid extracted and the timing of amniocentesis, with greater volumes needed in earlier stages of pregnancy.

The Effect of Self-Reported Race on Noninvasive Prenatal Screening Test Characteristics.

Low fetal fraction (FF) on cell-free DNA (cfDNA)-based noninvasive prenatal screening (NIPS) is a common etiology for indeterminate results. As maternal Black race is implicated as a risk factor for low FF and more indeterminate results, we sought to evaluate this association. This was a single-institution, retrospective cohort study of cfDNA-based NIPS performed between May 2017 and May 2022 with complete clinical data abstraction. We compared FF, indeterminate rates, and total cfDNA concentration among self-reported Black, White, and Other groups from NIPS results from 2017 to 2022 with full clinical data abstraction. Using linear regression and interaction testing, we evaluated associations between self-reported race, FF, indeterminate rate, and total cfDNA concentration. In total, 1,591 participants met the inclusion criteria; 70.8% (n = 1,126) self-identified as White, 6.9% (n = 110) as Black, and 22.3% (n = 355) self-identified with another race. Mean FF was not different between the White, Black, or Other groups (11.8 vs. 11.2 vs. 11.7%, respectively, p = 0.52). This remained true after adjusting for body mass index (BMI), gestational age (GA) at draw, and fetal sex (all p > 0.17). Interaction testing for FF and total cfDNA by race with BMI, GA at draw, and fetal sex demonstrated no effect modification. In our population, maternal self-identified race, particularly Black race, does not affect FF. Biological plausibility for race-based differences on clinical tests requires ongoing thoughtful consideration. · NIPS is widely used to screen for fetal aneuploidy.. · FF is an important test metric, and low FF is associated with adverse outcomes, like aneuploidy.. · In existing studies, Black race is implicated as a risk factor for lower FF.. · Our study found no differences in FF between groups by self-reported race.. · Biological plausibility for race-based differences on clinical tests requires ongoing consideration..

Should the sex of the fetus be considered when administering antenatal corticosteroids to preterm fetuses?

We aimed to determine whether the effect of antenatal corticosteroids (ANS) differs in male and female fetuses without anomalies born before 32 weeks in terms of mortality and short-term morbidity. This single-center retrospective study included infants born before 32 weeks' gestation and admitted to the neonatal intensive care unit between January 1, 2018, and December 31, 2020. The study included 210 infants with a median gestational age of 28.6 weeks (24-31.6), a birth weight of 1065 g (445-2165), and an ANS use rate of 80%. Compared to female fetuses exposed to ANS, male fetuses exposed to ANS had a lower mortality rate (23% and 11%, respectively, p = 0.038), but there were no differences in intraventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis, respiratory distress syndrome, and APGAR scores of 1st and 5th but an increased rate of bronchopulmonary dysplasia (moderate/severe) (p = 0.008). In addition, the mortality rate was similar in exposed and unexposed female fetuses (p = 0.850). Enzyme activities and steroid levels in the placenta might be different in male and female fetuses, which could explain the results of ANS administration. In our study, we have shown that ANS has no effect on mortality in female fetuses younger than 32 weeks. Future studies may focus on adjusting the administration of ANS based on fetal sex, altering the dose or taking fetal sex into account when performing ANS.

Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity.

Maternal obesity puts the offspring at high risk of developing obesity and cardio-metabolic diseases in adulthood. Here, using a mouse model of maternal high-fat diet (HFD)-induced obesity, we show that whole body fat content of the offspring of HFD-fed mothers (Off-HFD) increases significantly from very early age when compared to the offspring regular diet-fed mothers (Off-RD). We have previously shown significant metabolic and immune perturbations in the bone marrow of newly-weaned offspring of obese mothers. Therefore, we hypothesized that lipid metabolism is altered in the bone marrow Off-HFD in newly-weaned offspring of obese mothers when compared to the Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from three-week-old offspring of regular and high fat diet-fed mothers. Diacylgycerols (DAGs), triacylglycerols (TAGs), sphingolipids and phospholipids, including plasmalogen, and lysophospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in offspring of obese mothers, suggesting reduced delivery of cholesterol to bone marrow cells. This was accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from three-week-old mice and conducted metabolomics, lipidomics, and transcriptomics analyses. The lipidomic profiles of these bone marrow myeloid cells were largely similar to that seen in bone marrow cells and included increases in DAGs and phospholipids alongside decreased TAGs, except for long-chain TAGs, which were significantly increased. Our data also revealed significant sex-dependent changes in amino acids and metabolites related to energy metabolism. Transcriptomic analysis revealed altered expression of genes related to major immune pathways including macrophage alternative activation, B-cell receptor signaling, TGFβ signaling, and communication between the innate and adaptive immune systems. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly-weaned offspring of obese mothers, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.

The Predictive Accuracy of Anogenital Distance and Genital Tubercle Angle for First-Trimester Fetal Sex Determination.

Early identification of fetal gender is crucial for managing gender-linked genetic disorders. This study aimed to evaluate the predictive performance of anogenital distance (AGD) and genital tubercle angle (GTA) for fetal sex determination during the first trimester. A multicenter retrospective cohort study was conducted on 312 fetal cases between 11 and 13 + 6 weeks of gestation from two tertiary hospitals. AGD and GTA measurements were taken from midsagittal plane images using ultrasound, with intra- and inter-reader reproducibility assessed. Binomial logistic regression and ROC curve analysis were employed to determine the diagnostic performance and optimal cutoff points. AGD had a mean of 7.16 mm in male fetuses and 4.42 mm in female fetuses, with a sensitivity of 88.8%, specificity of 94.4%, and an area under the ROC curve (AUC) of 0.931 (95% CI: 0.899-0.962) using 5.74 mm as a cutoff point. For GTA, the mean was 35.90 degrees in males and 21.57 degrees in females, with a sensitivity of 92%, specificity of 84.7%, and an AUC of 0.932 (95% CI: 0.904-0.961) using 28.32 degrees as a cutoff point. The reproducibility results were excellent for AGD (intra-operator ICC = 0.938, inter-operator ICC = 0.871) and moderate for GTA (intra-operator ICC = 0.895, inter-operator ICC = 0.695). The findings suggest that AGD and GTA are reliable markers for early fetal sex determination, with AGD showing higher reproducibility. The findings highlight the feasibility and accuracy of these non-invasive sonographic markers and their potential usefulness in guiding timely interventions and enhancing the management of gender-linked genetic conditions.

Sexually dimorphic DNA methylation and gene expression patterns in human first trimester placenta

BackgroundFetal sex and placental development impact pregnancy outcomes and fetal–maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies.MethodsPregnant subjects were recruited in late first trimester (weeks 10–14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas.ResultsMethylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate < 0.05, including 89 (59%) hypermethylated in females. Probe cg17612569 (GABPA, ATP5J) was the most significant CpG site, hypermethylated in males. There were 11 differentially methylated regions affected by fetal sex, with transcription factors ZNF300 and ZNF311 most significantly hypermethylated in males and females, respectively. RNA-sequencing identified 152 genes significantly sexually dimorphic at false discovery rate < 0.05. The 151 DMPs were associated with 18 genes with gene downregulation (P < 0.05) in the direction of hypermethylation, including 2 genes significant at false discovery rate < 0.05 (ZNF300 and CUB and Sushi multiple domains 1, CSMD1). Both genes, as well as Family With Sequence Similarity 228 Member A (FAM228A), showed significant correlation between DNA methylation and sexually dimorphic gene expression, though FAM228A DNA methylation was less sexually dimorphic. Comparison with other sex differences studies found that cg17612569 is male-hypermethylated across gestation in placenta and in human blood up to adulthood.ConclusionsOverall, sex dimorphic differential methylation with associated differential gene expression in the first trimester placenta is small, but there remain significant genes that may be regulated through methylation leading to differences in the first trimester placenta.

Fetal sex effects on maternal health can now be tested via randomization: A first-in-class illustration in cows on glucoregulatory outcomes

BackgroundThe maternal-offspring relationship, such as whether fetal sex influences maternal health, is essential to explore to advance prenatal and maternal health. While associations exist between fetal sex and maternal health outcomes, it is unclear whether these reflect a causal relationship. ObjectiveTo demonstrate that fetal sex can be randomly assigned to test the causal effect of fetal sex on maternal outcomes. MethodsHolstein dairy cows were stratified and randomized using sealed opaque envelopes to be artificially inseminated with either X- or Y-sorted bull semen until 40 cows became pregnant. Monthly body weight measurements were recorded, and an intravenous glucose tolerance test was performed 30 days before the expected calving day. The primary outcome was insulin area under the curve (AUC), and secondary outcomes were clearance rate, half-life, and AUC for glucose, insulin, and non-esterified fatty acid concentrations. An intention-to-treat (ITT) approach using multiple imputation was employed for primary analysis, and an as-treated (AT) approach was used for secondary analysis. ResultsWe demonstrated that we could successfully randomize the assignment of fetal sex to dams and test for causal effects of fetal sex on glucoregulatory outcomes using dairy cows as a model. Insulin AUC was not statistically different between groups (ITT p = 0.857, AT p = 0.874), and other outcomes were also not statistically different (p > 0.05). ConclusionWe demonstrated that causal effects of fetal sex on maternal outcomes can be causally tested in dairy cows. Our study did not provide statistical evidence to support an effect of fetal sex on maternal glucose-related outcomes.

Induced abortion after advent of fetal sex detection technology and child sex at birth

BackgroundNational level Sex Ratio at Birth (SRB) is normal in Bangladesh despite its patriarchal social structures, strong son preference, and low fertility level, widely recognized as preconditions for Gender-Biased Sex Selection (GBSS). To better understand this anomaly, we examine the trend in SRB in a sub-district in Bangladesh and assess the impact of the introduction of fetal sex-detection technology and the history of induced abortion on child sex using longitudinal data.MethodsWe have used secondary data collected routinely by icddr, b’s Matlab Health and Demographic Surveillance System (HDSS) between 1982 and 2018. All births occurring during this period (N = 206,390) were included in the analyses. We calculated the SRB and used multivariate logistic regression analyses to assess the likelihood of birth of a male child before and after the introduction of ultrasonogram in Matlab.ResultsOverall, SRB was within the natural limit (106) during 1982–2018 in Matlab. SRB among women with a history of induced abortion was 109.3 before the introduction of ultrasonography in 2001 and 113.5 – after 2001. Women’s history of induced abortion prior to introduction of ultrasonogram (1982–2000) increased the likelihood of birth of a male child 1.06 times (AOR 1.06; 95% CI- 1.01–1.11). In the period after, however, this likelihood was 1.08 (AOR 1.08; 95% CI- 1.02–1.15).ConclusionsIn a context with normal SRB, it was found to be skewed among women who had induced abortion. SRB was relatively more skewed among such women after the advent of ultrasonogram compared to a period without ultrasonogram. Moreover, induced abortion after introduction of fetal sex determination technology increased the likelihood of birth of a male child. These findings suggest the plausibility of GBSS in a sub-group. Further research is needed, particularly in regions with skewed SRB to examine whether GBSS is indeed a threat to Bangladesh.