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

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

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

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

Assessing the validity of the Long-Term Conditions Questionnaire (LTCQ) in women during pregnancy and the first year following birth

Background: The aim of this study was to validate a generic patient-reported outcome measure, the Long-Term Conditions Questionnaire (LTCQ), among pregnant and postpartum women living with a pre-existing long-term condition (LTC). Methods: Cognitive interviews were conducted with women who were currently pregnant or had given birth within the past year and living with a pre-existing LTC (n=11) and with healthcare professionals working in maternal care (n=11) to explore the acceptability of LTCQ items. An online survey was subsequently administered among women who were pregnant or had given birth within the past year and living with a pre-existing LTC (n=718). Tests of validity were performed including assessing correlations between the LTCQ and reference measures, the Well-being in Pregnancy (WiP) Questionnaire and the EuroQol EQ-5D-5L. Internal consistency was assessed using the Cronbach’s alpha statistic. Results: All LTCQ items were considered relevant and appropriate for use with women who were pregnant or had given birth within the past year. The most commonly reported LTC among the online survey sample (n=718) was a mental health condition (n=350, 48.7%) followed by joint, bone and connective tissues (n= 212, 29.5%) and gastrointestinal (n=143, 19.9%) condition. Data indicated LTCQ scores behaved in a predictable pattern, demonstrating poorer scores for women reporting a greater number of LTCs; mean (SD) scores, one LTC= 61.86 (17.8), two LTCs= 55.29 (16.0), three LTCs= 49.84 (15.52) and four LTCs= 44.94 (12.2). Poorer scores were also reported for women living with at least one mental health condition compared to those reporting no mental health condition, mean score = 66.18 (SD 16.7) v 48.64 (SD 13.3), p< 0.001 respectively. As anticipated, LTCQ scores demonstrated significant correlations in the expected direction with both the EQ-5D-5L and WiP scores. For all LTCQ items, the Cronbach’s alpha statistic was 0.93. Conclusion: Data presented here indicate that the LTCQ, which assesses living well with one or more LTC, is suitable for use among pregnant and postpartum women, from both the woman’s perspective and from the perspectives of maternity healthcare professionals. Use of the LTCQ would facilitate the identification of unmet needs within this high-risk cohort and support the exploration of how LTCs may affect women throughout the pregnancy and post-natal period. Understanding unmet needs within this cohort of women provides an opportunity to link up specialist care within maternity services and enhance personalised care

Postpartum haemorrhage and risk of cardiovascular disease in later life: A population‐based record linkage cohort study

Objective: To investigate the association between postpartum haemorrhage (PPH) and subsequent cardiovascular disease. Design: Population‐based retrospective cohort study, using record linkage between Aberdeen Maternity and Neonatal Databank (AMND) and Scottish healthcare data sets. Setting: Grampian region, Scotland. Population: A cohort of 70 904 women who gave birth after 24 weeks of gestation in the period 1986–2016. Methods: We used extended Cox regression models to investigate the association between having had one or more occurrences of PPH in any (first or subsequent) births (exposure) and subsequent cardiovascular disease, adjusted for sociodemographic, medical, and pregnancy and birth‐related factors. Main Outcome Measures: Cardiovascular disease identified from the prescription of selected cardiovascular medications, hospital discharge records or death from cardiovascular disease. Results: In our cohort of 70 904 women (with 124 795 birth records), 25 177 women (36%) had at least one PPH. Compared with not having a PPH, having at least one PPH was associated with an increased risk of developing cardiovascular disease, as defined above, in the first year after birth (adjusted hazard ratio, aHR 1.96; 95% confidence interval, 95% CI 1.51–2.53; p < 0.001). The association was attenuated over time, but strong evidence of increased risk remained at 2–5 years (aHR 1.19, 95% CI 1.11–1.30, P < 0.001) and at 6–15 years after giving birth (aHR 1.17, 95% CI 1.05–1.30, p = 0.005). Conclusions: Compared with women who have never had a PPH, women who have had at least one episode of PPH are twice as likely to develop cardiovascular disease in the first year after birth, and some increased risk persists for up to 15 years