TMEM8C-mediated fusion is regionalized and regulated by NOTCH signalling during foetal myogenesis.

The location and regulation of fusion events within skeletal muscles during development remain unknown. Using the fusion marker myomaker (Mymk), named TMEM8C in chicken, as a readout of fusion, we identified a co-segregation of TMEM8C-positive cells and MYOG-positive cells in single-cell RNA-sequencing datasets of limbs from chicken embryos. We found that TMEM8C transcripts, MYOG transcripts and the fusion-competent MYOG-positive cells were preferentially regionalized in central regions of foetal muscles. We also identified a similar regionalization for the gene encoding the NOTCH ligand JAG2 along with an absence of NOTCH activity in TMEM8C+ fusion-competent myocytes. NOTCH function in myoblast fusion had not been addressed so far. We analysed the consequences of NOTCH inhibition for TMEM8C expression and myoblast fusion during foetal myogenesis in chicken embryos. NOTCH inhibition increased myoblast fusion and TMEM8C expression and released the transcriptional repressor HEYL from the TMEM8C regulatory regions. These results identify a regionalization of TMEM8C-dependent fusion and a molecular mechanism underlying the fusion-inhibiting effect of NOTCH in foetal myogenesis. The modulation of NOTCH activity in the fusion zone could regulate the flux of fusion events.

Prenatal assessment of brain malformations on neuroimaging: an expert panel review.

Brain malformations represent a heterogeneous group of abnormalities of neural morphogenesis, often associated with aberrations of neuronal connectivity and brain volume. Prenatal detection of brain malformations requires a clear understanding of embryology and developmental morphology through the various stages of gestation. This expert panel review is written with the central aim of providing an easy-to-understand roadmap to improve prenatal detection and characterization of structural malformations based on the current understanding of normal and aberrant brain development. The utility of each available neuroimaging modality including prenatal multiplanar neurosonography, anatomical magnetic resonance imaging (MRI), and advanced MRI techniques, as well as further insights from post-mortem imaging have been highlighted for every developmental stage.

Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association.

BACKGROUND AND AIMS: Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. METHODS: Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. RESULTS: Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. CONCLUSIONS: The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.

SERPINA11 related novel serpinopathy - A perinatal lethal disorder.

SERPINA11 is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily, with unknown expression pattern and functional significance. We report a perinatal lethal phenotype in two foetuses from the same family associated with a biallelic loss of function variant in SERPINA11, and provide functional evidence to support its candidature as a Mendelian disorder. The SERPINA11 variant-associated foetal phenotype is characterised by gross and histopathological features of extracellular matrix disruption. Western blot and immunofluorescence analyses revealed SERPINA11 expression in multiple mouse tissues, with pronounced expression in the bronchiolar epithelium. We observed a significant decrease in SERPINA11 immunofluorescence in the affected foetal lung compared with a healthy gestation-matched foetus. Protein expression data from HEK293T cell lines following site-directed mutagenesis support the loss of function nature of the variant. Transcriptome analysis from the affected foetal liver indicated the possibility of reduced SERPINA11 transcript abundance. This novel serpinopathy appears to be a consequence of the loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.

Maternal pre-pregnancy BMI and reproductive health in adult sons: a study in the Danish National Birth Cohort.

STUDY QUESTION: Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons? SUMMARY ANSWER: Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity. WHAT IS KNOWN ALREADY: Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons. STUDY DESIGN, SIZE, DURATION: A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019, was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1058 adult sons (median age 19 years, 2 months), born 1998-2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons' birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: We found no consistent associations between maternal pre-pregnancy BMI and semen characteristics or testes volume. Sons of mothers with higher pre-pregnancy BMI had higher oestradiol and lower SHBG levels, both in a dose-dependent manner. Sons of mothers with pre-pregnancy obesity (≥30 kg/m2) had higher LH levels and a higher FAI than sons born by mothers with normal pre-pregnancy BMI (18.5-24.9 kg/m2). The mediation analyses suggested that the effect of maternal pre-pregnancy BMI on higher levels of oestrogen, LH, and FAI was partly mediated by the sons' birthweight, in addition to adult fat mass and BMI measured at the clinical examination, whereas most of the effect on lower levels of SHBG was primarily mediated by the sons' own fat mass and BMI. Paternal BMI was not a strong confounder of the associations in this study. LIMITATIONS, REASONS FOR CAUTION: This study was based in a population-based cohort with a low prevalence of overweight and obesity in both mothers and adult sons. Some men (10%) had blood for reproductive hormone assessment drawn in the evening. While several potential confounding factors were accounted for, this study's inherent risk of residual and unmeasured confounding precludes provision of causal estimates. Therefore, caution should be given when interpreting the causal effect of maternal BMI on sons' reproductive health. WIDER IMPLICATIONS OF THE FINDINGS: Given the widespread occurrence of overweight and obesity among pregnant women, it is imperative to thoroughly examine the potential consequences for reproductive hormone levels in adult sons. The potential effects of maternal pre-pregnancy obesity on sons' reproductive hormone profile may potentially be partly avoided by the prevention of overweight and obesity in the sons. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University, Independent Research Fund Denmark (9039-00128B), and the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Endocrine disruption and male reproductive disorders: unanswered questions.

Maternal exposure to endocrine-disrupting chemicals (EDCs) in human pregnancy is widely considered as an important cause of adverse changes in male reproductive health due to impaired foetal androgen production/action. However, the epidemiological evidence supporting this view is equivocal, except for certain phthalates, notably diethyl hexyl phthalate (DEHP). Maternal phthalate exposure levels associated with adverse reproductive changes in epidemiological studies are several thousand-fold lower than those needed to suppress foetal androgen production in rats, and direct studies using human foetal testis tissue show no effect of high phthalate exposure on androgen production. This conundrum is unexplained and raises fundamental questions. Human DEHP exposure is predominantly via food with highest exposure associated with consumption of a Western style (unhealthy) diet. This diet is also associated with increased exposure to the most common EDCs, whether persistent (chlorinated or fluorinated chemicals) or non-persistent (phthalates, bisphenols) compounds, which are found at highest levels in fatty and processed foods. Consequently, epidemiological studies associating EDC exposure and male reproductive health disorders are confounded by potential dietary effects, and vice versa. A Western diet/lifestyle in young adulthood is also associated with low sperm counts. Disentangling EDC and dietary effects in epidemiological studies is challenging. In pregnancy, a Western diet, EDC exposure, and maternal living in proximity to industrial sites are all associated with impaired foetal growth/development due to placental dysfunction, which predisposes to congenital male reproductive disorders (cryptorchidism, hypospadias). While the latter are considered to reflect impaired foetal androgen production, effects resulting from foetal growth impairment (FGI) are likely indirect. As FGI has numerous life-long health consequences, and is affected by maternal lifestyle, research into the origins of male reproductive disorders should take more account of this. Additionally, potential effects on foetal growth/foetal testis from the increasing use of medications in pregnancy deserves more research attention.

When the liver is in poor condition, so is the heart - cardiac remodelling in MASH mouse models.

Metabolic dysfunction-associated steatohepatitis (MASH) confers a risk for cardiovascular diseases in patients. Animal models may help exploring the mechanisms linking liver and heart diseases. Hence, we explored the cardiac phenotype in 2 MASH mouse models: foz/foz mice fed a high fat diet (HFD) for 24 or 60 weeks and C57BL/6J mice fed a high fat-, high cholesterol-, and high fructose diet for 60 weeks. Angiotensin II (AngII) was used as an additional cardiovascular stressor for 4 weeks in 10 weeks HFD-fed foz/foz mice. Foz/foz mice with fibrosing MASH developed cardiac hypertrophy with adverse cardiac remodelling not seen in WT similarly fed the HFD. AngII caused hypertension and upregulated the expression of genes contributing to pathological cardiac hypertrophy (Nppa, Myh7) more severely so in foz/foz mice than in controls. After 60 weeks of HFD, while liver disease had progressed to burn-out non steatotic MASH with hepatocellular carcinoma in 50% of the animals, the cardiomyopathy did not. In an independent model (C57BL/6J mice fed a fat, cholesterol and fructose rich diet), moderate fibrosing MASH is associated with cardiac fibrosis and dysregulation of genes involved in pathological remodelling (Col1a1, Col3a1, Vim, Myh6, Slc2a1). Thus, animals with MASH present consistent adverse structural changes in the heart with no patent alteration of cardiac function even when stressed with exogenous AngII. Liver disease, and likely not overfeeding or aging alone, is associated with this cardiac phenotype. Our findings support foz/foz mice as suitable for studying links between MASH and heart structural changes ahead of heart failure.

Anaemia in the first trimester and poor physiological plasma expansion during pregnancy negatively impact foetal weight and newborn anthropometrics: An observational cohort study in Tanzania.

OBJECTIVES: Anaemia during pregnancy is a major health challenge affecting pregnancy outcome worldwide. The objectives of this study were to investigate the impact of severe-moderate anaemia in the first trimester, as well as changes in haemoglobin during pregnancy among non-anaemic women, on foetal weight, placental blood flow and newborn anthropometrics. METHODS: In a prospective cohort study, 346 women residing in rural Tanzania were followed throughout pregnancy with serial ultrasound and newborn anthropometrics assessed within 24 h of delivery. Associations between placental blood flow, foetal weight and newborn anthropometrics with either first trimester severe-moderate anaemia (haemoglobin≤9.5 g/dL) or changes in haemoglobin from the first to the third trimester among non-anaemic women, were assessed by mixed model regression and multiple linear regression, adjusting for maternal and foetal co-variables. Foetal weights and birthweight were converted to z-scores using a population based sex-specific weight reference. RESULTS: Severe-moderate anaemia in the first trimester was associated with significantly reduced foetal weight z-scores (adjusted mean difference (aMD) -0.44 (95% CI -0.81, -0.07)) and newborn anthropometric indices (birth weight z-score aMD -0.55 (-0.9, -0.13), abdominal circumference aMD -11 mm (95% CI -20, -3)). There were no association between first trimester severe-moderate anaemia and placental blood flow. Among women who were non-anaemic in the first trimester, women with the least reduction in haemoglobin (Δ ≥ -0.3 g/dL) delivered significantly smaller newborns (birthweight z-score aMD -0.55 (-0.91, -0.20), abdominal circumference aMD -10 mm (95% CI -17, -3), compared to women with the greatest reduction (Δ haemoglobin ≤ -1.4 g/dL)). CONCLUSIONS: Severe-moderate anaemia in early pregnancy was associated with smaller newborn anthropometrics which was reflected in smaller mean foetal weights in the second and third trimester. Furthermore, among women who were non-anaemic in the first trimester, there was an association between smaller newborn anthropometrics and limited haemoglobin decrease during pregnancy, possibly reflecting insufficient plasma expansion.

Maternal exercise during pregnancy modulates genotoxicity caused by high fructose consumption in mice offspring.

Pregnancy is a period that is characterized by several metabolic and physiological changes and requires special attention, especially with regard to the relationship between feeding and foetal development. Therefore, the objective of this study was to evaluate whether the practice of voluntary physical exercise (VPE) in combination with chronic consumption of fructose (FRU) from the beginning of life and/or until the gestational period causes genotoxic changes in pregnant females and in their offspring. Seventy Swiss female mice received FRU in the hydration bottle and/or practiced VPE for 8 weeks (prepregnancy/pregnancy). After the lactation period, the offspring groups were separated by sex. It was observed that the consumption of FRU affected the food consumption, serum concentration of FRU, and glycemic profile in the mothers and that the VPE decreases these parameters. In addition, FRU was genotoxic in the mothers' peripheral tissues and VPE had a preventive effect on these parameters. The offspring showed changes in food consumption, serum FRU concentration, and body weight, in addition to an increase in the adiposity index in male offspring in the FRU (FRU) group and a decrease in the FRU + VPE group. FRU leads to hepatic steatosis in the offspring and VPE was able to decrease the area of steatosis. In addition, FRU led to genotoxicity in the offspring and VPE was able to modulate this effect, reducing damages. In conclusion, we observed that all interventions with VPE had nutritional, genetic, and biochemical benefits of the mother and her offspring.

Disease severity in subsequent pregnancies with RhD immunization: A nationwide cohort.

BACKGROUND AND OBJECTIVES: To evaluate the severity of haemolytic disease of the foetus and newborn (HDFN) in subsequent pregnancies with RhD immunization and to identify predictive factors for severe disease. MATERIALS AND METHODS: Nationwide prospective cohort study, including all pregnant women with RhD antibodies. All women with at least two pregnancies with RhD antibodies and RhD-positive foetuses were selected. The main outcome measure was the severity of HDFN in the first and subsequent pregnancy at risk. A subgroup analysis was performed for the group of women where RhD antibodies developed after giving birth to an RhD-positive child and thus after receiving anti-D at least twice (group A) or during the first pregnancy at risk for immunization (group B). RESULTS: Sixty-two RhD immunized women with a total of 150 RhD-positive children were included. The severity of HDFN increased for the whole group significantly in the subsequent pregnancy (p < 0.001), although it remained equal or even decreased in 44% of women. When antibodies were already detected at first trimester screening in the first immunized pregnancy, after giving birth to an RhD-positive child (group A), severe HDFN in the next pregnancy was uncommon (22%). Especially when no therapy or only non-intensive phototherapy was indicated during the first immunized pregnancy (6%) or if the antibody-dependent cell-mediated cytotoxicity result remained <10%. Contrarily, women with a negative first trimester screening and RhD antibodies detected later during the first pregnancy of an RhD-positive child (group B), often before they had ever received anti-D prophylaxis, were most prone for severe disease in a subsequent pregnancy (48%). CONCLUSION: RhD-mediated HDFN in a subsequent pregnancy is generally more severe than in the first pregnancy at risk and can be estimated using moment of antibody detection and severity in the first immunized pregnancy. Women developing antibodies in their first pregnancy of an RhD-positive child are at highest risk of severe disease in the next pregnancy.

Pharmacokinetic study of erlotinib in a pregnant woman with advanced non-small cell lung cancer and observation of the effects on the child growth.

AIMS: The aim of the study is to report the clinical and pharmacological observations from a pregnant patient treated with erlotinib in the second and third trimesters of pregnancy. METHODS: Maternal and neonatal blood levels and safety of erlotinib and its metabolites were evaluated. Child development was monitored for 6 years. RESULTS: A 31-year-old woman with stage IV lung adenocarcinoma with EGFR exon19 deletion began treatment with erlotinib 150 mg/day at 17 weeks of gestation. Although foetal growth retardation and oligohydramnios were observed at several times during the pregnancy, treatment was continued due to the severity of the maternal presentation, with ongoing foetal monitoring. The foetus seemed to tolerate and recover well without specific interventions. A healthy baby boy was delivered at 37 weeks gestation. The child grew and developed without any obvious issues. At last follow-up, at age 6 years, he was attending school at a grade appropriate for his age without health or developmental problems. Blood levels of erlotinib were 397-856 ng/mL at 18-37 weeks of gestation and 1190 ng/mL at 8 weeks postpartum. The blood concentration ratios of OSI-413-to-erlotinib ranged from 0.167 to 0.253 at 18-37 weeks of gestation, excluding 24 weeks, and 0.131 at 8 weeks postpartum. The maternal-to-foetal transfer rate of erlotinib, OSI-420 and OSI-413 were 24.5, 34.8 and 20.3%, respectively. CONCLUSION: Erlotinib use during the second and third trimester of pregnancy did not seem to cause any untoward effects on the developing foetus, or any long-lasting effects that could be detected during 6 years of follow-up of the child.

Paternal and maternal birthweight and offspring risk of macrosomia at term gestations: A nationwide population study.

BACKGROUND: There is a paucity of data on whether parents' macrosomia (birthweight ≥4500 g) status influences the risk of macrosomia in the offspring. The role of maternal overweight in the generational effect of macrosomia is not known. OBJECTIVE: To estimate the risk of macrosomia by parental birthweight at term and evaluate if this risk varied with maternal body mass index (BMI, kg/m2) early in pregnancy. METHODS: We used data from the Medical Birth Registry of Norway on all singleton term births (37-42 gestational weeks) during 1967-2017. The primary exposure was parental macrosomia, and the outcome was macrosomia in the second generation. The secondary exposure was maternal BMI. We used binomial regression to calculate relative risk (RR) with a 95% confidence interval. We assessed potential unmeasured confounding and selection bias using a probabilistic bias analysis and performed analyses with and without imputation for variables with missing values. RESULTS: The data included 647,957 singleton parent-offspring trios born at term. The prevalence of macrosomia was 3.2% (n = 41,396) in the parental generation and 4.0% (n = 25,673) in the offspring generation. Macrosomia in parents was associated with an increased risk of macrosomia in offspring, with the RR for both parents were born macrosomic being 6.53 (95% confidence interval [CI] 5.31, 8.05), only mother macrosomic 3.37 (95% CI 3.17, 3.57) and only father macrosomic RR 2.22 (95% CI 2.12, 2.33). These risks increased by maternal BMI in early pregnancy: if both parents were born macrosomic, 17% of infants were macrosomic among mothers with normal BMI. If both parents were macrosomic and the mothers were obese, 31% of offspring were macrosomic. Macrosomia-related adverse outcomes did not differ with parental macrosomia status. CONCLUSIONS: Parents' weight at birth and maternal BMI appear to be strongly associated with macrosomia in the offspring delivered at term gestations.

Unveiling sex bias and adverse neonatal outcomes in ultrasound estimation of gestational age: A population-based cohort study.

BACKGROUND: Gestational age estimation by second-trimester ultrasound biometry introduces systematic errors due to sex differences in early foetal growth, consequently increasing the risk of adverse neonatal outcomes. Ultrasound estimation earlier in pregnancy may reduce this bias. OBJECTIVES: To investigate the distribution of sex ratio by gestational age and estimate the risk of adverse outcomes in male foetuses born early-term and female foetuses born post-term by first- and second-trimester ultrasound estimations. METHODS: This population-based study compared two cohorts of births with gestational age based on first- and second-trimester ultrasound in the Medical Birth Registry of Norway between 2016 and 2020. We used a log-binomial regression model to estimate adjusted relative risk (RR) with 95% confidence interval (CI) for Apgar score <7 at 5 min, umbilical artery pH <7.05, neonatal intensive care unit (NICU) admission and respiratory morbidity in relation to foetal sex. RESULTS: The sex ratio at birth in gestational weeks 36-43 showed less male predominance in pregnancies estimated in first compared to second trimester. Any adverse outcome was registered in 627 of 4470 male infants born in gestational weeks 37-38 and 618 of 6406 females born ≥41 weeks. Male infants born in weeks 37-38 had lower risk of NICU admission (RR 0.76, 95% CI 0.58, 0.99), Apgar score <7 at 5 min (RR 0.63, 95% CI 0.28, 1.41) and respiratory morbidity (RR 0.68, 95% CI 0.37, 1.25) in first- compared to second-trimester estimations. Female infants estimated in first trimester born ≥41 weeks had lower risk of umbilical artery pH <7.05, NICU admissions and respiratory morbidity; however, CIs were wide. CONCLUSIONS: Early ultrasound estimation of gestational age may reduce the excess risk of adverse neonatal outcomes and highlight the role of foetal sex and the timing of ultrasound assessment in the clinical evaluation of preterm and post-term pregnancies.

The clinical performance and population health impact of birthweight-for-gestational age indices at term gestation.

BACKGROUND: The assessment of birthweight for gestational age and the identification of small- and large-for-gestational age (SGA and LGA) infants remain contentious, despite the recent creation of the Intergrowth 21st Project and World Health Organisation (WHO) birthweight-for-gestational age standards. OBJECTIVE: We carried out a study to identify birthweight-for-gestational age cut-offs, and corresponding population-based, Intergrowth 21st and WHO centiles associated with higher risks of adverse neonatal outcomes, and to evaluate their ability to predict serious neonatal morbidity and neonatal mortality (SNMM) at term gestation. METHODS: The study population was based on non-anomalous, singleton live births between 37 and 41 weeks' gestation in the United States from 2003 to 2017. SNMM included 5-min Apgar score <4, neonatal seizures, need for assisted ventilation, and neonatal death. Birthweight-specific SNMM was modelled by gestational week using penalised B-splines. The birthweights at which SNMM odds were minimised (and higher by 10%, 50% and 100%) were estimated, and the corresponding population, Intergrowth 21st, and WHO centiles were identified. The clinical performance and population impact of these cut-offs for predicting SNMM were evaluated. RESULTS: The study included 40,179,663 live births and 991,486 SNMM cases. Among female singletons at 39 weeks' gestation, SNMM odds was lowest at 3203 g birthweight, and 10% higher at 2835 g and 3685 g (population centiles 11th and 82nd, Intergrowth centiles 17th and 88th and WHO centiles 15th and 85th). Birthweight cut-offs were poor predictors of SNMM, for example, the cut-offs associated with 10% and 50% higher odds of SNMM among female singletons at 39 weeks' gestation resulted in a sensitivity, specificity, and population attributable fraction of 12.5%, 89.4%, and 2.1%, and 2.9%, 98.4% and 1.3%, respectively. CONCLUSIONS: Reference- and standard-based birthweight-for-gestational age indices and centiles perform poorly for predicting adverse neonatal outcomes in individual infants, and their associated population impact is also small.

Haemorrhage of human foetal cortex associated with SARS-CoV-2 infection.

Maternal viral infection and immune response are known to increase the risk of altered development of the foetal brain. Given the ongoing global pandemic of coronavirus disease 2019 (COVID-19), investigating the impact of SARS-CoV-2 on foetal brain health is of critical importance. Here, we report the presence of SARS-CoV-2 in first and second trimester foetal brain tissue in association with cortical haemorrhages. SARS-CoV-2 spike protein was sparsely detected within progenitors and neurons of the cortex itself, but was abundant in the choroid plexus of haemorrhagic samples. SARS-CoV-2 was also sparsely detected in placenta, amnion and umbilical cord tissues. Cortical haemorrhages were linked to a reduction in blood vessel integrity and an increase in immune cell infiltration into the foetal brain. Our findings indicate that SARS-CoV-2 infection may affect the foetal brain during early gestation and highlight the need for further study of its impact on subsequent neurological development.

Pregnancy, antiseizure medications and unexplained intrauterine foetal death.

OBJECTIVE: To assess the role of antiseizure medication (ASM) regimens and other factors in relation to the occurrence of intrauterine foetal death (IUFD) in pregnant women with epilepsy (WWE) enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (APR). RESULTS: IUFDs occurred in 70 (3.01 %) of 2,323 prospective pregnancies from WWE with known outcomes in the APR. Factors associated with IUFD occurrence included older maternal age, enrolment in the APR at an earlier stage of pregnancy, history of pregnancies which did not result in livebirths, parental history of foetal malformations, and maternal use of carbamazepine, lamotrigine or ethosuximide. Individual ASM dosages were not associated with IUFD occurrence. Relative to no exposure, the risk of IUFD increased with the increasing number of ASMs used in combination (2 ASMs: relative risk, RR = 5.45 [95 % CI: 0.73-41.80]; 3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), >3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), but this finding was attenuated after adjusting for other factors implicated in IUFD occurrence. Several ASM pairs were associated with an increased risk of IUFD relative to no exposure, but these associations were lost after accounting for confounders. CONCLUSIONS: Although it is possible that prenatal ASM exposure may increase the risk of IUFD, other non-pharmacological factors are more relevant to the occurrence to IUFD in pregnant WWE.

Diagnosis of single umbilical artery and risk of foetal congenital malformations by prenatal ultrasound: a retrospective study.

BACKGROUND: Single umbilical artery (SUA) is strongly associated with foetal structural abnormalities; however, the exact pattern of this association has not been described. We aimed to investigate the occurrence of malformations in singleton pregnancies with SUA in China and to study the association between the absent side of the umbilical artery and foetal malformations. METHODS: This was a retrospective study of singleton pregnancies for which routine first-trimester anatomical screening was performed at 11+ 0-13+ 6 gestational weeks and, if the pregnancy continued, a second-trimester scan was performed at 20+ 0-24+ 0 weeks. Data were extracted from records at the referral centre, the Obstetrics and Gynecology Hospital of Fudan University, between January 2011 and April 2019 (n = 47,894). Using logistic regression, the odds ratios (OR) with 95% confidence intervals (CIs) were calculated for malformations associated with SUA. RESULTS: The incidence of SUA in our study was 2.0% (970/47,894). Of all foetuses with SUA, 387 (39.9%) had structural malformations. The malformation type varied, with cardiovascular complications being the most common. A robust association was observed between SUA and oesophageal stenosis or atresia (OR: 25.33), followed by cardiovascular (OR: 9.98-24.02), scoliosis (OR: 18.62), genitourinary (OR: 2.45-15.66), and brain malformations (OR: 4.73-9.12). The absence of the left umbilical artery (n = 445, 45.9%) was consistent with that of the right umbilical artery (n = 431, 44.4%). Furthermore, a significantly higher rate of an absent right than the left umbilical artery (p<0.01) was observed in SUA with foetal abnormalities than in SUA with no malformations. CONCLUSIONS: Overall, we observed a higher risk of various specific malformations in foetuses with SUA, and a strong association between SUA and oesophageal stenosis or atresia. The absence of the right umbilical artery was most common in foetuses with SUA and structural malformations. This study provides a reference for ultrasonographers in conducting foetal structural screening for pregnant women with SUA.

A first trimester prediction model and nomogram for gestational diabetes mellitus based on maternal clinical risk factors in a resource-poor setting.

BACKGROUND: The implementation of universal screening for Gestational Diabetes Mellitus (GDM) is challenged by several factors key amongst which is limited resources, hence the continued reliance on risk factor-based screening. Effective identification of high-risk women early in pregnancy may enable preventive intervention. This study aimed at developing a GDM prediction model based on maternal clinical risk factors that are easily assessable in the first trimester of pregnancy in a population of Nigerian women. METHODS: This was a multi-hospital prospective observational cohort study of 253 consecutively selected pregnant women from which maternal clinical data was collected at 8-12 weeks gestational age. Diagnosis of GDM was made via a one-step 75-gram Oral Glucose Tolerance Test (OGTT) at 24-28 weeks of gestation. A GDM prediction model and nomogram based on selected maternal clinical risk factors was developed using multiple logistic regression analysis, and its performance was assessed by Receiver Operator Curve (ROC) analysis. Data analysis was carried out using Statistical Package for Social Sciences (SPSS) version 25 and Python programming language (version 3.0). RESULTS: Increasing maternal age, higher body mass index (BMI), a family history of diabetes mellitus in first-degree relative and previous history of foetal macrosomia were the major predictors of GDM. The model equation was: LogitP = 6.358 - 0.066 × Age - 0.075 × First trimester BMI - 1.879 × First-degree relative with diabetes mellitus - 0.522 × History of foetal macrosomia. It had an area under the receiver operator characteristic (ROC) curve (AUC) of 0.814 (95% CI: 0.751-0.877; p-value < 0.001), and at a predicted probability threshold of 0.745, it had a sensitivity of 79.2% and specificity of 74.5%. CONCLUSION: This first trimester prediction model reliably identifies women at high risk for GDM development in the first trimester, and the nomogram enhances its practical applicability, contributing to improved clinical outcomes in the study population.

Gestational diabetes mellitus in patients undergoing assisted reproductive techniques or conceiving spontaneously: an analysis on maternal and foetal outcomes.

PURPOSE: With the rise of medically assisted reproductive techniques (ART) the number of pregnancies complicated by gestational diabetes mellitus (GDM) has increased. The aim of this study was to evaluate retrospectively the outcomes of pregnancies complicated by GDM who conceive trough ART (cases) compared to those who conceived spontaneously (controls). METHODS: In 670 women with GDM, 229 cases and 441 controls, followed by the Diabetology of Padua, between 2010-2022, clinical-metabolic maternal characteristics and maternal-foetal outcomes were evaluated. RESULTS: As for the maternal clinical-metabolic characteristics, plasma glucose levels at 60' and 120' under oral glucose tolerance test (OGTT) at time of diagnosis were significantly higher in cases (177.4 ± 31.1 vs 170.9 ± 34.1 mg/dl, p = 0.016; 151.5 ± 32.2 vs 144.0 ± 33.4 mg/dl, p = 0.005 respectively). Furthermore, at diagnosis, cases show higher levels of total cholesterol (257 ± 53 mg/dl vs 246 ± 52 mg/dl; p = 0.012) and triglycerides (199.8 ± 83.2 mg/dl vs 184.9 ± 71.3 mg/dl; p = 0.02) compared to controls. As for maternal outcomes, thyroid disfunction, was recorded in a higher percentage in case (21.4% vs 14.3%; p = 0.008), as well as, the frequency of cesarean section (50.3% vs 41.2%; p = 0.038) and twin pregnancies (16.2% vs 2.5%; p < 0.001). As for neonatal outcomes, there were no statistically significant differences, except for the birth weight of the second twin, which was significantly lower in cases (2268 ± 536 vs 2822 ± 297 g; p = 0.002). No other significant differences were found. CONCLUSION: This study showed no meaningful differences in the outcomes of GDM pregnancies who were conceived with ART compared to that arose spontaneously as the patients were promptly diagnosed and treated.

Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research.

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.