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

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

Outcomes at five to eight years of age for children with Hirschsprung's disease.

OBJECTIVE: This study describes core outcomes of Hirschsprung's disease (HD) in a UK-wide cohort of primary school-aged children. DESIGN: A prospective cohort study conducted from 1 October 2010 to 30 September 2012. Outcomes data were collected from parents and clinicians when children were 5-8 years of age, and combined with data collected at birth, and 28 days and 1 year post diagnosis. SETTING: All 28 UK and Irish paediatric surgical centres. PARTICIPANTS: Children with histologically proven HD diagnosed at <6 months of age. MAIN OUTCOME MEASURES: NETS1HD core outcomes. RESULTS: Data were returned for 239 (78%) of 305 children. Twelve children (5%) died prior to 5 years of age.Of the 227 surviving children, 30 (13%) had a stoma and 21 (9%) were incontinent of urine. Of the 197 children without a stoma, 155 (79%) maintained bowel movements without enemas/washouts, while 124 (63%) reported faecal incontinence. Of the 214 surviving children who had undergone a pull-through operation, 95 (44%) underwent ≥1 unplanned reoperation. 89 unplanned reoperations (27%) were major/complex.Of the 83 children with returned PedsQL scores, 37 (49%) had quality of life scores, and 31 (42%) had psychological well-being scores, that were ≥1 SD lower than the reference population mean for children without HD. CONCLUSION: This study gives a realistic picture of population outcomes of HD in primary school-aged children in the UK/Ireland. The high rates of faecal incontinence, unplanned procedures and low quality of life scores are sobering. Ensuring clinicians address the bladder, bowel and psychological problems experienced by children should be a priority

What is the relationship between deprivation, modifiable factors and childhood deaths: A cohort study using the English National Child Mortality Database

Objectives The aim of this analysis is to identify the patterns of social deprivation and childhood mortality; and identify potential points where public health, social and education interventions, or health policy may be best targeted.Design Decile of deprivation and underlying population distribution was derived using Office for National Statistics data. The risk of death was then derived using a Poisson regression model, calculating the increasing risk of death for each increasing deprivation decile.Setting England.Participants 2688 deaths before 18 years of age reviewed between April 2019 and March 2020.Main outcome measures The relationship between deprivation and risk of death; for deaths with, and without modifiable factors.Results There was evidence of increasing mortality risk with increase in deprivation decile, with children in the least deprived areas having a mortality of 13.25 (11.78–14.86) per 100 000 person-years, compared with 31.14 (29.13–33.25) in the most deprived decile (RR 1.08 (95% CI 1.07 to 1.10)); with the gradient of risk stronger in children who died with modifiable factors than those without (RR 1.12 (95% CI 1.09 to 1.15)) vs (RR 1.07 (95% CI 1.05 to 1.08)). Deprivation subdomains of employment, adult education, barriers to housing and services, and indoor living environments appeared to be the most important predictors of child mortalityConclusions There is a clear gradient of increasing child mortality across England as measures of deprivation increase; with a striking finding that this varied little by area, age or other demographic factor. Over one-fifth of all child deaths may be avoided if the most deprived half of the population had the same mortality as the least deprived. Children dying in more deprived areas may have a greater proportion of avoidable deaths. Adult employment, and improvements to housing, may be the most efficient place to target resources to reduce these inequalities