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

Ethnic and socioeconomic variation in cause-specific preterm infant mortality by gestational age at birth: national cohort study

Objective: To describe ethnic and socioeconomic variation in cause-specific infant mortality of preterm babies by gestational age at birth. Design: National birth cohort study. Setting: England and Wales 2006–2012. Subjects: Singleton live births at 24–36 completed weeks’ gestation (n=256 142). Outcome measures: Adjusted rate ratios for death in infancy by cause (three groups), within categories of gestational age at birth (24–27, 28–31, 32–36 weeks), by baby’s ethnicity (nine groups) or area deprivation score (Index of Multiple Deprivation quintiles). Results: Among 24–27 week births (5% of subjects; 47% of those who died in infancy), all minority ethnic groups had lower risk of immaturity-related death than White British, the lowest rate ratios being 0.63 (95% CI 0.49 to 0.80) for Black Caribbean, 0.74 (0.64 to 0.85) for Black African and 0.75 (0.60 to 0.94) for Indian. Among 32–36 week births, all minority groups had higher risk of death from congenital anomalies than White British, the highest rate ratios being 4.50 (3.78 to 5.37) for Pakistani, 2.89 (2.10 to 3.97) for Bangladeshi and 2.06 (1.59 to 2.68) for Black African; risks of death from congenital anomalies and combined rarer causes (infection, intrapartum conditions, SIDS and unclassified) increased with deprivation, the rate ratios comparing the most with the least deprived quintile being, respectively, 1.54 (1.22 to 1.93) and 2.05 (1.55 to 2.72). There was no evidence of socioeconomic variation in deaths from immaturity-related conditions. Conclusions: Gestation-specific preterm infant mortality shows contrasting ethnic patterns of death from immaturity-related conditions in extremely-preterm babies, and congenital anomalies in moderate/late-preterm babies. Socioeconomic variation derives from congenital anomalies and rarer causes in moderate/late-preterm babies. Future research should examine biological origins of extremely preterm birth

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

Impact of maternal risk factors on ethnic disparities in maternal mortality:a national population-based cohort study

BackgroundEthnic disparities in maternal mortality are consistently reported. This study aimed to investigate the contribution of known risk factors including age, socioeconomic status, and medical comorbidities to observed ethnic disparities in the United Kingdom (UK).MethodsA cohort of all women who died during or up to six weeks after pregnancy in the UK 2009–2019 were identified through national surveillance. No single denominator population included data on all risk factors, therefore we used logistic regression modelling to compare to 1) routine population birth and demographic data (2015–19) (routine data comparator) and 2) combined control groups of four UK Obstetric Surveillance System studies (UKOSS) control comparator)).FindingsThere were 801 maternal deaths in the UK between 2009 and 2019 (White: 70%, Asian: 13%, Black: 12%, Chinese/Other: 3%, Mixed: 2%). Using the routine data comparator (n = 3,519,931 maternities) to adjust for demographics, including social deprivation, women of Black ethnicity remained at significantly increased risk of maternal death compared with women of white ethnicity (adjusted OR 2.43 (95% Confidence Interval 1.92–3.08)). The risk was greatest in women of Caribbean ethnicity (aOR 3.55 (2.30–5.48)). Among women of White ethnicity, risk of mortality increased as deprivation increased, but women of Black ethnicity had greater risk irrespective of deprivation. Using the UKOSS control comparator (n = 2210), after multiple adjustments including smoking, body mass index, and comorbidities, women of Black and Asian ethnicity remained at increased risk (aOR 3.13 (2.21–4.43) and 1.57 (1.16–2.12) respectively).InterpretationKnown risk factors do not fully explain ethnic disparities in maternal mortality. The impact of socioeconomic deprivation appears to differ between ethnic groups

Impact of maternal risk factors on ethnic disparities in maternal mortality: a national population-based cohort study

Background Ethnic disparities in maternal mortality are consistently reported. This study aimed to investigate the contribution of known risk factors including age, socioeconomic status, and medical comorbidities to observed ethnic disparities in the United Kingdom (UK). Methods A cohort of all women who died during or up to six weeks after pregnancy in the UK 2009–2019 were identified through national surveillance. No single denominator population included data on all risk factors, therefore we used logistic regression modelling to compare to 1) routine population birth and demographic data (2015–19) (routine data comparator) and 2) combined control groups of four UK Obstetric Surveillance System studies (UKOSS) control comparator)). Findings There were 801 maternal deaths in the UK between 2009 and 2019 (White: 70%, Asian: 13%, Black: 12%, Chinese/Other: 3%, Mixed: 2%). Using the routine data comparator (n = 3,519,931 maternities) to adjust for demographics, including social deprivation, women of Black ethnicity remained at significantly increased risk of maternal death compared with women of white ethnicity (adjusted OR 2.43 (95% Confidence Interval 1.92–3.08)). The risk was greatest in women of Caribbean ethnicity (aOR 3.55 (2.30–5.48)). Among women of White ethnicity, risk of mortality increased as deprivation increased, but women of Black ethnicity had greater risk irrespective of deprivation. Using the UKOSS control comparator (n = 2210), after multiple adjustments including smoking, body mass index, and comorbidities, women of Black and Asian ethnicity remained at increased risk (aOR 3.13 (2.21–4.43) and 1.57 (1.16–2.12) respectively). Interpretation Known risk factors do not fully explain ethnic disparities in maternal mortality. The impact of socioeconomic deprivation appears to differ between ethnic groups. Funding This research is funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme, conducted through the Policy Research Unit in Maternal and Neonatal Health and Care, PR-PRU-127-21202

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

A new method of prenatal alcohol classification accounting for dose, pattern, and timing of exposure: Improving our ability to examine fetal effects from low to moderate exposure

Background: When examining the association between prenatal alcohol exposure and fetal effects, the timing and intensity of exposure have been ignored in epidemiological studies. The effect of using dose, pattern and timing of consumption (“composite” method) was investigated in this study, to examine the association between prenatal alcohol exposure and fetal effects. Methods: The composite method resulted in six categories of exposure (abstinent, low, moderate, binge <weekly, binge 1–2×/week and heavy). The odds of language delay and child behaviour problems were calculated for the composite method and then compared with an analysis using averaged estimates of <1 and 1+ drinks per day and with stratification by quantity ignoring dose per occasion. Data used for the analyses were from a 10% random sample of non-Indigenous women delivering a live infant in Western Australia (1995–1997). Participants from the 1995-1996 cohort were invited to participate in an 8-year longitudinal survey (78% response rate n=2224; 85% were followed-up at 2 years, 73% at 5 years and 61% at 8 years). Results: The effect of moderate and binge levels of exposure was only evident with the composite method; anxiety/depression following first-trimester moderate exposure (OR 2.24, 95% CI 1.16 to 4.34), and following late pregnancy moderate (aggressive behaviour OR 1.93, 95% CI 0.91 to 4.09) and binge (language delay OR 3.00, 95% CI 0.90 to 9.93) exposures. Results for heavy levels of exposure were similar with each method. The estimates for late pregnancy were imprecise due to small numbers. Conclusion: The composite method of classification more closely reflects real-life drinking patterns and better discriminates maternal drinking than the other methods, particularly low, moderate and binge levels