Parent-of-origin effects in SOX2 anophthalmia syndrome

PURPOSE: Sex determining region Y (SRY)-box 2 (SOX2) anophthalmia syndrome is an autosomal dominant disorder manifesting as severe developmental eye malformations associated with brain, esophageal, genital, and kidney abnormalities. The syndrome is usually caused by de novo mutations or deletions in the transcription factor SOX2. To investigate any potential parental susceptibility factors, we set out to determine the parent of origin of the mutations or deletions, and following this, to determine if birth order or parental age were significant factors, as well as whether mutation susceptibility was related to any sequence variants in cis with the mutant allele. METHODS: We analyzed 23 cases of de novo disease to determine the parental origin of SOX2 mutations and deletions using informative single nucleotide polymorphisms and a molecular haplotyping approach. We examined parental ages for SOX2 mutation and deletion cases, compared these with the general population, and adjusted for birth order. RESULTS: Although the majority of subjects had mutations or deletions that arose in the paternal germline (5/7 mutation and 5/8 deletion cases), there was no significant paternal bias for new mutations (binomial test, p=0.16) or deletions (binomial test, p=0.22). For both mutation and deletion cases, there was no significant association between any single nucleotide polymorphism allele and the mutant chromosome (p>0.05). Parents of the subjects with mutations were on average older at the birth of the affected child than the general population by 3.8 years (p=0.05) for mothers and 3.3 years (p=0.66) for fathers. Parents of the subjects with deletions were on average younger than the general population by 3.0 years (p=0.17) for mothers and 2.1 years (p=0.19) for fathers. Combining these data, the difference in pattern of parental age between the subjects with deletions and mutations was evident, with a difference of 6.5 years for mothers (p=0.05) and 5.0 years for fathers (p=0.22), with the mothers and fathers of subjects with mutations being older than the mothers and fathers of subjects with deletions. We observed that 14 of the 23 (61%) affected children were the first-born child to their mother, with 10/15 of the mutation cases (66%) and 4/8 deletion cases (50%) being first born. This is in comparison to 35% of births with isolated congenital anomalies overall who are first born (p=0.008). CONCLUSIONS: Sporadic SOX2 mutations and deletions arose in both the male and female germlines. In keeping with several genetic disorders, we found that SOX2 mutations were associated with older parental age and the difference was statistically significant for mothers (p=0.05), whereas, although not statistically significant, SOX2 deletion cases had younger parents. With the current sample size, there was no evidence that sequence variants in cis surrounding SOX2 confer susceptibility to either mutations or deletions

Planned mode of birth after previous caesarean section and women's use of psychotropic medication in the first year postpartum:a population-based record linkage cohort study

Background: Policy in many high-income settings supports giving pregnant women with previous caesarean section a choice between an elective repeat caesarean section (ERCS) or planning a vaginal birth after previous caesarean (VBAC), provided they have no contraindications to VBAC. Despite the potential for this choice to influence women's mental health, evidence about the associated effect to counsel women and identify potential targets for intervention is limited. This study investigated the association between planned mode of birth after previous caesarean and women's subsequent use of psychotropic medications. Methods: A population-based cohort study of 31 131 women with one or more previous caesarean sections who gave birth to a term singleton in Scotland between 2010 and 2015 with no prior psychotropic medications in the year before birth was conducted using linked Scottish national datasets. Cox regression was used to investigate the association between planned mode of birth and being dispensed psychotropic medications in the first year postpartum adjusted for socio-demographic, medical, pregnancy-related factors and breastfeeding. Results: Planned VBAC (n = 10 220) compared to ERCS (n = 20 911) was associated with a reduced risk of the mother being dispensed any psychotropic medication [adjusted hazard ratio (aHR) 0.85, 95% confidence interval (CI) 0.78–0.92], an antidepressant (aHR 0.83, 95% CI 0.76–0.90), and at least two consecutive antidepressants (aHR 0.83, 95% CI 0.75–0.91) in the first year postpartum. Conclusions: Women giving birth by ERCS were more likely than those having a planned VBAC to be dispensed psychotropic medication including antidepressants in the first year postpartum. Further research is needed to establish the reasons behind this new finding

Variations in neonatal mortality, infant mortality, preterm birth and birth weight in England and Wales according to ethnicity and maternal country or region of birth: an analysis of linked national data from 2006 to 2012.

BACKGROUND: Risks of adverse birth outcomes in England and Wales are relatively low but vary across ethnic groups. We aimed to explore the role of mother's country of birth on birth outcomes across ethnic groups using a large population-based linked data set. METHODS: We used a cohort of 4.6 million singleton live births in England and Wales to estimate relative risks of neonatal mortality, infant mortality and preterm birth, and differences in birth weight, comparing infants of UK-born mothers to infants whose mothers were born in their countries or regions of ethnic origin, or elsewhere. RESULTS: The crude neonatal and infant death risks were 2.1 and 3.2 per 1000, respectively, the crude preterm birth risk was 5.6% and the crude mean birth weight was 3.36 kg. Pooling across all ethnic groups, infants of mothers born in their countries or regions of ethnic origin had lower adjusted risks of death and preterm birth, and higher gestational age-adjusted mean birth weights than those of UK-born mothers. White British infants of non-UK-born mothers had slightly lower gestational age-adjusted mean birth weights than White British infants of UK-born mothers (mean difference -3 g, 95% CI -5 g to -0.3 g). Pakistani infants of Pakistan-born mothers had lower adjusted risks of neonatal death (adjusted risk ratio (aRR) 0.84, 95% CI 0.72 to 0.98), infant death (aRR 0.84, 95% CI 0.75 to 0.94) and preterm birth (aRR 0.85, 95% CI 0.82 to 0.88) than Pakistani infants of UK-born Pakistani mothers. Indian infants of India-born mothers had lower adjusted preterm birth risk (aRR 0.91, 95% CI 0.87 to 0.96) than Indian infants of UK-born Indian mothers. There was no evidence of a difference by mother's country of birth in risk of birth outcomes among Black infants, except Black Caribbean infants of mothers born in neither the UK nor their region of origin, who had higher neonatal death risks (aRR 1.71, 95% CI 1.06 to 2.76). CONCLUSION: This study highlights evidence of better birth outcomes among UK-born infants of non-UK-born minority ethnic group mothers, and could inform the design of future interventions to reduce the risks of adverse birth outcomes through improved targeting of at-risk groups

Planned mode of delivery after previous cesarean section and short-term maternal and perinatal outcomes : A population-based record linkage cohort study in Scotland

The authors would like to acknowledge the support of the eDRIS Team (National Services Scotland) for their involvement in obtaining approvals and provisioning and linking data and the use of the secure analytical platform within the National Safe Haven. Funding: KEF is funded by a National Institute for Health Research (NIHR) Doctoral Research Fellowship (DRF-2016-09-078) for this research project. This paper presents independent research. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Joint contribution of socioeconomic circumstances and ethnic group to variations in preterm birth, neonatal mortality and infant mortality in England and Wales: a population-based retrospective cohort study using routine data from 2006 to 2012.

OBJECTIVES: This study aimed to describe the variation in risks of adverse birth outcomes across ethnic groups and socioeconomic circumstances, and to explore the evidence of mediation by socioeconomic circumstances of the effect of ethnicity on birth outcomes. SETTING: England and Wales. PARTICIPANTS: The data came from the 4.6 million singleton live births between 2006 and 2012. EXPOSURE: The main exposure was ethnic group. Socioeconomic circumstances, the hypothesised mediator, were measured using the Index of Multiple Deprivation (IMD), an area-level measure of deprivation, based on the mother's place of residence. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were birth outcomes, namely: neonatal death, infant death and preterm birth. We estimated the slope and relative indices of inequality to describe differences in birth outcomes across IMD, and the proportion of the variance in birth outcomes across ethnic groups attributable to IMD. We investigated mediation by IMD on birth outcomes across ethnic groups using structural equation modelling. RESULTS: Neonatal mortality, infant mortality and preterm birth risks were 2.1 per 1000, 3.2 per 1000 and 5.6%, respectively. Babies in the most deprived areas had 47%-129% greater risk of adverse birth outcomes than those in the least deprived areas. Minority ethnic babies had 48%-138% greater risk of adverse birth outcomes compared with white British babies. Up to a third of the variance in birth outcomes across ethnic groups was attributable to differences in IMD, and there was strong statistical evidence of an indirect effect through IMD in the effect of ethnicity on birth outcomes. CONCLUSION: There is evidence that socioeconomic circumstances could be contributing to the differences in birth outcomes across ethnic groups

Outcomes for women admitted for labour care to alongside midwifery units in the UK following a postpartum haemorrhage in a previous pregnancy: A national population-based cohort and nested case-control study using the UK Midwifery Study System (UKMidSS)

Background Women who have experienced a postpartum haemorrhage (PPH) ‘requiring treatment or transfusion’ are typically advised to plan birth in obstetric-led settings in subsequent pregnancies. Many UK alongside midwifery units (AMU) admit women for labour care following a previous PPH. We aimed to describe outcomes in women admitted for labour care to AMUs following a previous PPH, compare outcomes with other multiparous women admitted to the same AMUs, and explore risk factors for recurrence. Methods A national cohort and nested case-control study using the UK Midwifery Study System (UKMidSS), between August 2018 and April 2019. Multivariable Poisson regression and logistic regression were performed to compare outcomes and investigate risk factors for recurrence. Findings Women who experienced a previous PPH were significantly more likely than comparison women to: have a PPH requiring transfer to obstetric care (4·2% vs. 2·4%, aRR=1·65, 95% CI 1·14–2·38), be transferred to obstetric care for any reason (17·8% vs 11·9%; aRR=1·41; 95% CI 1·09–1·83), and have any PPH≥ 500 ml (22·7% vs 11·1%, aRR=1·86, 95% CI 1·49–2·32). Among women with a previous PPH, previous blood loss > 1500 ml; uterotonics for previous PPH; Caesarean associated with previous PPH; gestation at admission and higher birthweight were independent risk factors for PPH. Conclusion Women considering birth in an AMU after a previous PPH should be advised that they are at increased risk of experiencing a subsequent PPH requiring transfer to obstetric care, compared with other multiparous women who have not had a PPH. The absolute risk of a subsequent PPH in this group is low and comparable to the overall risk of having a PPH among women having a spontaneous vaginal birth in England

Placenta accreta spectrum - variations in clinical practice and maternal morbidity between UK and France : a population-based comparative study

SM’s DPhil was funded by the Medical Research Council. PACCRETA was funded by PACCRETA was funded by the French Health Ministry under its Clinical Research Hospital Program (grant number: AOR12156) and by the Angers University Hospital.Peer reviewedPublisher PD