In patients with proximal hypospadias, often no genetic cause is identified despite extensive genetic testing. Many genes involved in sex development encode transcription factors with strict timing and dosing of the gene products. We hypothesised that there might be recurrent differences in DNA methylation in boys with hypospadias and that these might differ between patients born small versus appropriate for gestational age. Genome-wide Methylated DNA sequencing (MeD-seq) was performed on 32bp LpnPI restriction enzyme fragments after RE-digestion in leucocytes from 16 XY boys with unexplained proximal hypospadias, one with an unexplained XX testicular disorder/difference of sex development (DSD) and twelve, healthy, sex- and age-matched controls. Five of seven differentially methylated regions (DMRs) between patients and XY controls were in the Long Intergenic Non-Protein Coding RNA 665 (LINC00665; CpG24525). Three patients showed hypermethylation of MAP3K1. Finally, no DMRs in XX testicular DSD associated genes were identified in the XX boy versus XX controls. In conclusion, we observed no recognizable epigenetic signature in 16 boys with XY proximal hypospadias and no difference between children born small versus appropriate for gestational age. Comparison to previous methylation studies in individuals with hypospadias did not show consistent findings, possibly due to the use of different inclusion criteria, tissues and methods.

BACKGROUND: In recent years, there has been a change in the conceptualization of foetal growth restriction (FGR), which has gone from being defined solely based on weight criteria to being defined and staged based on Doppler criteria. The aim of our study was to evaluate neonatal risk in a cohort of neonates with moderate to severe early-onset FGR defined by Doppler criteria.
METHODS: We conducted a multicentre prospective cohort study in a cohort of neonates with early-onset foetal growth restriction and abnormal Doppler findings and a control cohort without Doppler abnormalities matched for sex and gestational age.
RESULTS: A total of 105 patients (50 cases, 55 controls) were included. We found a higher frequency of respiratory morbidity in the FGR group, with an increased need of surfactant (30% vs. 27.3%; OR, 5.3 [95% CI, 1.1-26.7]), an increased need for supplemental oxygen (66% vs. 49.1%; OR, 5.6 [95% CI, 1.5-20.5]), and a decreased survival without bronchopulmonary dysplasia (70 vs. 87.3%; OR, 0.16 [95% CI, 0.03-0.99]). Patients with FGR required a longer length of stay and more days of parenteral nutrition and had a higher incidence of haematological abnormalities such as neutropenia and thrombopenia. The lactate level at birth was higher in the severe FGR subgroup (6.12 vs. 2.4 mg/dL; P = .02).
CONCLUSIONS: The diagnosis of early-onset moderate to severe FGR defined by Doppler criteria carries a greater risk of respiratory, nutritional and haematological morbidity, independently of weight and gestational age. These patients, therefore, should be considered at increased risk compared to constitutionally small for gestational age preterm infants or preterm infants without FGR.

UNASSIGNED: A new conceptual term, small and vulnerable newborns (SVN), bringing preterm birth, small for gestational age (SGA), or low birth weight (LBW) together is being advocated for assessing whether a child is at high risk.
UNASSIGNED: According to the new conceptual term, the increasing incidence of high-risk newborns (from 9.82% to 10.96%) has been observed among 2,005,408 newborns over the period from 2013 to 2022, which is higher than using any of the three definitions of SVN. Maternal age ≥35, primiparity, and multiple births are high risks for SVN.
UNASSIGNED: The new conceptual framework should be used to better assess the number of high-risk newborns. Attention should be paid to multiple births to prevent preterm-related SVN. To reduce term newborns who are SGA, we need to be concerned not only with multiple pregnancies but also with first-time mothers.

OBJECTIVE: This study was undertaken to examine the association between different patterns of antiseizure medication (ASM) use during pregnancy and adverse obstetric outcomes (preterm birth, low birth weight [LBW], and small for gestational age [SGA]).
METHODS: This retrospective cohort study used the Birth Certificate Application and National Health Insurance data in Taiwan (January 1, 2004 through December 31, 2018). We retrieved weekly ASM among pregnant women with epilepsy who were prepregnancy chronic users and used group-based trajectory modeling to identify distinct patterns of use. Logistic regressions were adopted to examine the association between patterns of ASM use and risk of preterm birth, LBW, and SGA. In addition, we revealed postnatal ASM utilization pattern among these prepregnancy chronic users as an exploratory study.
RESULTS: Of 2175 pregnant women with epilepsy, we identified four patterns of ASM use during pregnancy: frequent and continuous (64.87%), frequent but discontinuous (7.08%), intermittent (19.72%), and intermittent and discontinuous users (8.32%). Compared to frequent and continuous users, the adjusted odds ratios for preterm birth in frequent but discontinuous, intermittent, and intermittent and discontinuous users were .83 (95% confidence interval [CI] = .47-1.48), .71 (95% CI = .47-1.05), and .88 (95% CI = .52-1.49), respectively. Similar results were observed for LBW and SGA. In the exploratory study, we found that most of our study subjects maintained the same patterns before and after delivery.
CONCLUSIONS: After considering duration and timing of exposure, our study did not find an association between four distinct patterns of ASM use and adverse obstetric outcomes among women with epilepsy. The findings suggested that optimal seizure control could be received for pregnant women with epilepsy after evaluating the risks and benefits.

Background Every antenatal woman and her treating doctor aim for a healthy newborn. In obstetrics, accurately determining the gestational age (GA) is a critical aspect of managing pregnancy and evaluating fetal growth and development. The transcerebellar diameter (TCD) is the greatest transverse measurement of the fetal cerebellum. The growth of the cerebellum is minimally affected by fluctuations in growth, making the TCD the most reliable measurement for predicting GA. The purpose of the present research is to determine the accuracy of TCD in estimating GA in the second and third trimesters of pregnancy. Materials and methods The study included 500 antenatal women at 18-40 weeks of gestation. We also measured TCD in addition to routine ultrasound parameters like biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). We used IBM SPSS Statistics for Windows, Version 22 (Released 2013; IBM Corp., Armonk, New York, United States) for statistical analysis. The collected data was subjected to statistical tests, including Pearson\'s correlation coefficient and coefficient of determination. We conducted a regression analysis and used correlation coefficients to compare each ultrasound-measured parameter with the GA. Results The current research demonstrates a significant linear relationship between the TCD and GA (r = 0.9865; p = 0.0001), a strong association between BPD and GA (r = 0.9541; p = 0.0001), between HC and GA (r = 0.9613; p = 0.0001), between AC and GA (r = 0.9489; p = 0.0001), and between FL and GA (r = 0.9697; p = 0.0001). TCD showed the best correlation with GA among all the biometric parameters. TCD showed a correct assessment of GA by the last menstrual period (LMP) in 479 (95.8%) antenatal women. Conclusion The current research concludes that the TCD can be utilized as an independent measure to determine GA in the second and third trimesters of pregnancy, particularly in cases where the LMP is unknown, no dating scan has been performed in the first trimester, initial assessment taking place in the third trimester and in fetuses with variations in head shape such as dolichocephaly and brachycephaly.

Background In obstetrics, accurately determining gestational age (GA) is a critical aspect of managing pregnancy and evaluating fetal growth and development. Intrauterine growth restriction (IUGR) is characterized by the failure of the fetus to reach its potential growth. Early detection of IUGR is crucial for optimal obstetric care to reduce fetal complications and neonatal morbidity and mortality. The purpose of the current research is to determine the role of transcerebellar diameter (TCD) and the TCD/abdominal circumference (AC) ratio in assessing fetal growth and diagnosing IUGR. Methods In the sample, there were 600 expectant mothers with GA exceeding 28 weeks. We measured TCD and AC and then calculated the TCD/AC ratio. We used IBM SPSS Statistics for Windows, V. 22.0 (IBM Corp., Armonk, NY), for statistical analysis. The data was subjected to statistical tests, including Pearson\'s correlation coefficient, coefficient of determination, and tests of validity. Results The current research demonstrates a strong linear correlation between TCD and GA. Additionally, there was no notable disparity in TCD measurements between normal and IUGR fetuses with the same GA. There was an insignificant relationship between the TCD/AC ratio and GA, with a constant TCD/AC ratio in the third trimester of pregnancy in normal fetuses. The mean TCD/AC ratio was 14.72±0.89 (mean±standard deviation), and a cut-off value of 16.5 was determined to diagnose IUGR. Conclusion TCD can serve as a reliable measure for GA estimation during the third trimester in pregnant women with uncertain last menstrual period (LMP) or no dating scan and IUGR fetuses. In diagnosing IUGR, the TCD/AC ratio has demonstrated greater sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The TCD/AC ratio is a GA-independent measure that can be used to diagnose IUGR.

Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n = 9) or saline (IUGR; n = 8) for 5 days during late gestation and compared to saline-infused controls (n = 11). Circulating eicosapentaenoic acid was 42% less (p < 0.05) for IUGR fetuses but was recovered in IUGR+EPA fetuses. The infusion did not improve placental function or fetal O2 but resolved the 67% greater (p < 0.05) circulating TNFα observed in IUGR fetuses. This improved myoblast function and muscle growth, as the 23% reduction (p < 0.05) in the ex vivo differentiation of IUGR myoblasts was resolved in IUGR+EPA myoblasts. Semitendinosus, longissimus dorsi, and flexor digitorum superficialis muscles were 24-39% lighter (p < 0.05) for IUGR but not for IUGR+EPA fetuses. Elevated (p < 0.05) IL6R and reduced (p < 0.05) β2 adrenoceptor content in IUGR muscle indicated enhanced inflammatory sensitivity and diminished β2 adrenergic sensitivity. Although IL6R remained elevated, β2 adrenoceptor deficits were resolved in IUGR+EPA muscle, demonstrating a unique underlying mechanism for muscle dysregulation. These findings show that fetal inflammation contributes to IUGR muscle growth deficits and thus may be an effective target for intervention.

Current evidence suggests that airborne pollutants have a detrimental effect on fetal growth through the emergence of small for gestational age (SGA) or term low birth weight (TLBW). The study\'s objective was to critically evaluate the available literature on the association between environmental pollution and the incidence of SGA or TLBW occurrence. A comprehensive literature search was conducted across Pubmed/MEDLINE, Web of Science, Cochrane Library, EMBASE, and Google Scholar using predefined inclusion and exclusion criteria. The methodology adhered to the PRISMA guidelines. The systematic review protocol was registered in PROSPERO with ID number: CRD42022329624. As a result, 69 selected papers described the influence of environmental pollutants on SGA and TLBW occurrence with an Odds Ratios (ORs) of 1.138 for particulate matter ≤ 10 μm (PM10), 1.338 for particulate matter ≤ 2.5 μm (PM2.5), 1.173 for ozone (O3), 1.287 for sulfur dioxide (SO2), and 1.226 for carbon monoxide (CO). All eight studies analyzed validated that exposure to volatile organic compounds (VOCs) is a risk factor for SGA or TLBW. Pregnant women in the high-risk group of SGA occurrence, i.e., those living in urban areas or close to sources of pollution, are at an increased risk of complications. Understanding the exact exposure time of pregnant women could help improve prenatal care and timely intervention for fetuses with SGA. Nevertheless, the pervasive air pollution underscored in our findings suggests a pressing need for adaptive measures in everyday life to mitigate worldwide environmental pollution.

Metformin, the most commonly prescribed drug for the treatment of diabetes, is increasingly used during pregnancy to address various disorders such as diabetes, obesity, preeclampsia, and metabolic diseases. However, its impact on neocortex development remains unclear. Here, we investigated the direct effects of metformin on neocortex development, focusing on ERK and p35/CDK5 regulation. Using a pregnant rat model, we found that metformin treatment during pregnancy induces small for gestational age (SGA) and reduces relative cortical thickness in embryos and neonates. Additionally, we discovered that metformin inhibits neural progenitor cell proliferation in the sub-ventricular zone (SVZ)/ventricular zone (VZ) of the developing neocortex, a process possibly mediated by ERK inactivation. Furthermore, metformin induces neuronal apoptosis in the SVZ/VZ area of the developing neocortex. Moreover, metformin retards neuronal migration, cortical lamination, and differentiation, potentially through p35/CDK5 inhibition in the developing neocortex. Remarkably, compensating for p35 through in utero electroporation partially rescues metformin-impaired neuronal migration and development. In summary, our study reveals that metformin disrupts neocortex development by inhibiting neuronal progenitor proliferation, neuronal migration, cortical layering, and cortical neuron maturation, likely via ERK and p35/CDK5 inhibition. Consequently, our findings advocate for caution in metformin usage during pregnancy, given its potential adverse effects on fetal brain development.

Inflammatory bowel diseases (IBD) are significantly associated with adverse pregnancy and neonatal outcomes, though the pathomechanism is yet unknown. To investigate the relationship between IBD and adverse pregnancy outcomes by comparing neonatal outcomes and placental histopathology in two matched groups of patients with and without IBD. In this retrospective study, data of all patients who gave birth between 2008-2021 and were diagnosed with IBD were reviewed and compared to a control group matching two control cases for every IBD case. Neonatal outcomes and placental pathology were compared between the groups. Compared to the control group (n=76), the placentas of patients with IBD (n=36) were characterized by significantly lower placental weight (p < 0.001), and higher rates of maternal vascular malperfusion lesions (MVM, p < 0.001) and maternal and fetal inflammatory response lesions (p < 0.001). Neonates of patients with IBD were more frequently small for gestational age (SGA) (p=0.01), with increased rates of need for phototherapy (p = 0.03), respiratory morbidity and NICU admission (p < 0.001 for both outcomes). Multivariate logistic regression analyses adjusting for possible confounders (including maternal age, gestational age, chronic hypertension, smoking, and thrombophilia) confirmed the independent association between IBD and composite MVM lesions (aOR 4.31, p < 0.001), maternal inflammatory responses (aOR 40.22, p < 0.001) and SGA infants (aOR 4.31, p = 0.013). IBD is associated with increased rates of placental histopathological lesions and adverse pregnancy outcomes, including SGA infants. These novel findings imply the role of placental malperfusion and inflammatory processes in pregnancy complications of IBD patients, which should be followed accordingly. Approval of local ethics committee # WOMC-0219-20.