Study protocol for two randomised controlled trials evaluating the effects of Cerclage in the reduction of extreme preterm birth and perinatal mortality in twin pregnancies with a short cervix or dilatation: the TWIN Cerclage studies.

INTRODUCTION: Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage. METHODS AND ANALYSIS: We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at <24 weeks of gestation and an asymptomatic short cervix of ≤25 mm or cervical dilatation will be randomly allocated (1:1) to both trials on vaginal cerclage and standard treatment according to the current Dutch Society of Obstetrics and Gynaecology guideline (no cerclage). Permuted blocks sized 2 and 4 will be used to minimise the risk of disbalance. The primary outcome measure is PTB of <28 weeks. Analyses will be by intention to treat. The first trial is to demonstrate a risk reduction from 25% to 10% in the short cervix group, for which 194 patients need to be recruited. The second trial is to demonstrate a risk reduction from 80% to 35% in the dilatation group and will recruit 44 women. A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committees in the Netherlands on 3/30/2023. Participants will be required to sign an informed consent form. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05968794.

'Not a goal, but a given': Neonatal care participation through parents' perspective, a cross-sectional study.

AIM: To explore parents' perspectives regarding participation in neonatal care, with focus on the family integrated care (FICare) model utilised as a tool to enhance parent-infant closeness. Additionally, we describe experiences in different architectural settings. METHODS: An online survey, categorised by four FICare pillars, was distributed through social media to parents of newborns hospitalised to Dutch neonatal wards between 2015 and 2020. Quantitative findings were summarised using descriptive statistics, while open-ended responses were thematically analysed. RESULTS: Among the 344 respondents (98% mothers), most reported feeling involved in care (315/340). However, 79% also felt separated from their infant (265/337). Irrespective of architectural settings, parents reported incomplete implementation of FICare pillars: 14% was invited to educational sessions (parent education), 51% discussed family-specific care plans (staff education), 21% was facilitated in connecting with veteran parents (psychosocial support) and 22% received couplet-care (environment). Although 65% of parents were invited to attend clinical rounds, 32% actively participated in decision making. Thematic analysis revealed fundamentals for feeling welcome on the ward, peer-to-peer support, psychosocial support and participation in clinical rounds. CONCLUSION: Overall, parents expressed satisfaction with participation in neonatal care. However, structural implementation of FICare lacks. Regardless of architecture, expanding parent participation beyond presence requires attention.

Opportunities and Challenges of Prognostic Models for Extremely Preterm Infants.

Predicting the short- and long-term outcomes of extremely preterm infants remains a challenge. Multivariable prognostic models might be valuable tools for clinicians, parents, and policymakers for providing accurate outcome estimates. In this perspective, we discuss the opportunities and challenges of using prognostic models in extremely preterm infants at population and individual levels. At a population level, these models could support the development of guidelines for decisions about treatment limits and may support policy processes such as benchmarking and resource allocation. At an individual level, these models may enhance prenatal counselling conversations by considering multiple variables and improving transparency about expected outcomes. Furthermore, they may improve consistency in projections shared with parents. For the development of prognostic models, we discuss important considerations such as predictor and outcome measure selection, clinical impact assessment, and generalizability. Lastly, future recommendations for developing and using prognostic models are suggested. Importantly, the purpose of a prognostic model should be clearly defined, and integrating these models into prenatal counselling requires thoughtful consideration.

Duration of breastfeeding and gender are associated with methylation of the LEPTIN gene in very young children.

BACKGROUND: Perinatal environmental factors have been associated with the metabolic programming of children and consequent disease risks in later life. Epigenetic modifications that lead to altered gene expression may be involved. Here, we study early life environmental and constitutional factors in association with the DNA methylation of leptin (LEP), a non-imprinted gene implicated in appetite regulation and fat metabolism. METHODS: We investigated maternal education, breastfeeding, and constitutional factors of the child at 17 mo of age. We measured the DNA methylation of LEP in whole blood and the concentration of leptin in serum. RESULTS: Duration of breastfeeding was negatively associated with LEP methylation. Low education (≤12 y of education) was associated with higher LEP methylation. Boys had higher birth weight and lower LEP methylation than girls. An inverse association was established between birth weight per SD increase (+584 g) and LEP methylation. High BMI and leptin concentration were associated with lower methylation of LEP. CONCLUSION: The early life environment and constitutional factors of the child are associated with epigenetic variations in LEP. Future studies must reveal whether breastfeeding and the associated decrease in LEP methylation is an epigenetic mechanism contributing to the protective effect of breastfeeding against obesity.

Congenital heart defects and parental occupational exposure to chemicals.

BACKGROUND: Congenital heart defects (CHDs) are the most common major malformations in newborns. In this study we examined the associations between the occurrence of CHDs in children and periconceptional occupational parental exposures to chemicals. METHODS: In an age-matched case-control study with standardized data collection at c. 15 months after birth, 424 mothers and 421 fathers of a child with CHD and 480 mothers and 477 fathers of a non-malformed child, filled out questionnaires on periconceptional general and job characteristics. A job exposure matrix, which links the information on job title and a description of work tasks to an expert judgement on exposure to chemicals in the workplace, was used. RESULTS: The overall prevalence of occupational exposure to chemicals was 5.0 in cases and 6.2% in controls for mothers [odds ratio (OR) adjusted = 0.92; 95% confidence interval (CI): 0.26-3.25], while 22.3 and 15.9% for fathers, respectively (OR adjusted = 1.23; 95% CI: 0.39-3.91). No association of maternal occupational exposure to chemicals with risk of CHDs was found. Paternal exposure to phthalates was associated with a higher incidence of CHDs in general (OR adjusted = 2.08; 95% CI: 1.27-3.40). Paternal exposure to phthalates was associated with perimembranous ventricular septal defect (OR adjusted = 2.84; 95% CI: 1.37-5.92), to polychlorinated compounds with atrioventricular septal defect (OR adjusted = 4.22; 95% CI: 1.23-14.42) and to alkylphenolic compounds with coarctation of the aorta (OR adjusted = 3.85; 95% CI: 1.17-12.67). CONCLUSIONS: Periconceptional paternal (but not maternal) occupational exposure to certain chemicals is associated with an increased risk of CHDs in children. The results, however, must be interpreted cautiously as exposure probabilities are a crude measure of exposure.

General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect.

OBJECTIVE: We sought to investigate maternal and child functional MDR1 C3435T polymorphism, periconception medication, folic acid use, and the risk of a congenital heart defect (CHD) in the offspring. STUDY DESIGN: MDR1 3435C>T genotyping was performed in 283 case triads (mother, father, child) and 308 control triads. Information on periconception medication and folic acid use was obtained through questionnaires. RESULTS: Mothers with MDR1 3435CT/TT genotype and using medication showed a significant association with the risk of a child with CHD (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3-4.3) compared to mothers with MDR1 3435CC genotype not using medication. This risk increased without folic acid use (OR, 2.8; 95% CI, 1.2-6.4), and decreased in folic acid users (OR, 1.7; 95% CI, 0.8-3.7). Children carrying the MDR1 3435CT/TT genotype and periconceptionally exposed to medication without folic acid did not show significant risks. CONCLUSION: Mothers carrying the MDR1 3435T allele, using medication without folic acid, are at nearly 3-fold increased risk for CHD in the offspring.

Congenital heart defects and biomarkers of methylation in children: a case-control study.

BACKGROUND: Derangements in the maternal methylation pathway, expressed by global hypomethylation and hyperhomocysteinemia, are associated with the risk of having a child with a congenital heart defect (CHD). It is not known whether periconception exposure to these metabolic derangements contributes to chromosome segregation and metabolic programming of this pathway in the foetus. DESIGN: In a Dutch population-based case-control study of 143 children with CHD and 186 healthy children, we investigated S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total homocysteine (tHcy), the vitamins folate and B12 and the functional single nucleotide polymorphisms in the folate gene MTHFR 677C>T and 1298A>C. Comparisons were made between cases and controls adjusting for age, medication, vitamin use and CHD family history. RESULTS: In the overall CHD group, the median concentrations of SAM (P = 0·011), folate in serum (P = 0·021) and RBC (P = 0·030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0·001), SAH (P = 0·012) and serum folate (P = 0·010) independent of carriership of MTHFR polymorphisms. Highest concentrations of SAM, SAH and folate RBC were observed in complex syndromic CHD. The subgroup of children with Down syndrome, however, showed significantly higher SAH (P = 0·037) and significantly lower SAM:SAH ratio (P = 0·034) compared with other complex CHD, suggesting a state of global hypomethylation. CONCLUSION: High concentrations of methylation biomarkers in very young children are associated with complex CHD. Down syndrome and CHD may be associated with a global hypomethylation status, which has to be confirmed in tissues and global DNA methylation in future studies.

Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child.

BACKGROUND: Countries worldwide recommend women planning pregnancy to use daily 400 microg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. METHODOLOGY/PRINCIPAL FINDINGS: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). CONCLUSIONS: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.