Women's experiences of being invited to participate in a case-control study of stillbirth - findings from the Midlands and North of England Stillbirth Study

Background: The Midlands and North of England Stillbirth Study (MiNESS) was a case-control study of women who had a stillbirth or who had an ongoing pregnancy. During the set up phase questions were raised about whether interviewing women within six weeks of a stillbirth and recruiting women who were still pregnant into a “stillbirth” study was acceptable. This led to the research questions “whether it is appropriate to ask women who have recently experienced a stillbirth to participate in research?” and “whether it is appropriate to ask pregnant women to participate in a research project looking at factors associated with stillbirth.” This nested study aimed to describe the opinions of women approached to participate in MiNESS to explore their views and experiences of a research project focussed on stillbirth. Methods: Semi- structured interviews were conducted at a single study site involved in MiNESS. Purposive sampling was used to obtain a sample of women who were approached following a stillbirth (case n = 6) and those who were approached during pregnancy who gave birth to a live born baby (control n = 6). These two groups of women were divided equally according to whether they participated in the main MiNESS questionnaire study and those who declined to do so (n = 3 in each group). Interview data were transcribed and analysed using thematic analysis to identify the most important factors in determining whether women participated in MiNESS. Results: The following themes emerged from the analysis: participants’ understanding of research; approach by researcher; wanting to help; stillbirth taboo. These themes are explored individually in the manuscript. Participants reported positive views about research and previous participation in research studies. Respondents valued an initial approach from a member of staff already known to them. The taboo around stillbirth was a barrier to participation for some women with ongoing pregnancies. Conclusions: Experiences and views regarding research differed between participants and non-participants in the MiNESS study. Participants reported a greater understanding of the importance and implications of clinical research. When designing future studies, the timing of approach, clarity of information and the person approaching potential participants should be considered to optimise recruitment

Maternal sleep practices and stillbirth: Findings from an international case‐control study

Background: Late stillbirth, which occurs ≥28 weeks’ gestation, affects 1.3‐8.8 per 1000 births in high‐income countries. Of concern, most occur in women without established risk factors. Identification of potentially modifiable risk factors that relate to maternal behaviors remains a priority in stillbirth prevention research. This study aimed to investigate, in an international cohort, whether maternal sleep practices are related to late stillbirth. Methods: An Internet‐based case‐control study of women who had a stillbirth ≥28 weeks’ gestation within 30 days before completing the survey (n = 153) and women with an ongoing third‐trimester pregnancy or who had delivered a live born child within 30 days (n = 480). Bivariate and multivariate logistic regressions were used to determine unadjusted and adjusted odds ratios (OR and aOR, respectively) with 95% confidence intervals (95% CIs) for stillbirth. Results: Sleeping >9 hours per night in the previous month was associated with stillbirth (aOR 1.75 [95% CI 1.10‐2.79]), as was waking on the right side (2.27 [1.31‐3.92]). Nonrestless sleep in the last month was also found to be associated with stillbirth (1.73 [1.03‐2.99]), with good sleep quality in the last month approaching significance (1.64 [0.98‐2.75]). On the last night of pregnancy, not waking more than one time was associated with stillbirth (2.03 [1.24‐3.34]). No relationship was found with going to sleep position during pregnancy, although very few women reported settling in the supine position (2.4%). Conclusions: Long periods of undisturbed sleep are associated with late stillbirth. Physiological studies of how the neuroendocrine and autonomic system pathways are regulated during sleep in the context of late pregnancy are warranted

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3.

BACKGROUND: Maternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression. METHOD: A diagnosis of depression during pregnancy was recorded from Manchester cohort participants' medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression. RESULTS: In a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively). CONCLUSIONS: This study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.The Manchester cohort was supported by Manchester National Institute for Health Research (NIHR) Biomedical Research. The Queen Charlotte’s cohort was supported by the Medical Research Council (MRC) (Eurostress), National Institutes of Health (R01MH073842) and the Genesis Research Trust. The MBAM cohort was supported by the Genesis Research Trust. A.B.J. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Grants (DTG) studentship and subsequently MRC project grant MR/M013960/1. S.J.T. was supported by BBSRC project grant BB/J015156/1. L.E.C. was supported by an Imperial College London Ph.D. studentship and both L.E.C. and P.G.R were supported by the NIHR Imperial Biomedical Research Centre

Breech presentation is associated with lower adolescent tibial bone strength

Summary We compared bone outcomes in adolescents with breech and cephalic presentation. Tibia bone mineral content, density, periosteal circumference, and cross-sectional moment of inertia were lower in breech presentation, and females with breech presentation had lower hip CSA. These findings suggest that prenatal loading may exert long-lasting influences on skeletal development. Introduction Breech position during pregnancy is associated with reduced range of fetal movement, and with lower limb joint stresses. Breech presentation at birth is associated with lower neonatal bone mineral content (BMC) and area, but it is unknown whether these associations persist into later life. Methods We examined associations between presentation at onset of labor, and tibia and hip bone outcomes at age 17 years in 1971 participants (1062 females) from a UK prospective birth cohort that recruited > 15,000 pregnant women in 1991–1992. Cortical BMC, cross-sectional area (CSA) and bone mineral density (BMD), periosteal circumference, and cross-sectional moment of inertia (CSMI) were measured by peripheral quantitative computed tomography (pQCT) at 50% tibia length. Total hip BMC, bone area, BMD, and CSMI were measured by dual-energy X-ray absorptiometry (DXA). Results In models adjusted for sex, age, maternal education, smoking, parity, and age, singleton/multiple births, breech presentation (n = 102) was associated with lower tibial cortical BMC (− 0.14SD, 95% CI − 0.29 to 0.00), CSA (− 0.12SD, − 0.26 to 0.02), BMD (− 0.16SD, − 0.31 to − 0.01), periosteal circumference (− 0.14SD, − 0.27 to − 0.01), and CSMI (− 0.11SD, − 0.24 to 0.01). In females only, breech presentation was associated with lower hip CSA (− 0.24SD, − 0.43 to 0.00) but not with other hip outcomes. Additional adjustment for potential mediators (delivery method, birthweight, gestational age, childhood motor competence and adolescent height and body composition) did not substantially affect associations with either tibia or hip outcomes. Conclusions These findings suggest that prenatal skeletal loading may exert long-lasting influences on skeletal size and strength but require replication

The CErebro Placental RAtio as indicator for delivery following perception of reduced fetal movements, protocol for an international cluster randomised clinical trial; the CEPRA study.

BACKGROUND: Routine assessment in (near) term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age. Although biometric measurements and cardiotocography are frequently used, it is known that these techniques have low sensitivity and specificity. In clinical practice this diagnostic uncertainty results in considerable 'over treatment' of women with healthy fetuses whilst truly compromised fetuses remain unidentified. The CPR is the ratio of the umbilical artery pulsatility index over the middle cerebral artery pulsatility index. A low CPR reflects fetal redistribution and is thought to be indicative of placental insufficiency independent of actual fetal size, and a marker of adverse outcomes. Its utility as an indicator for delivery in women with reduced fetal movements (RFM) is unknown. The aim of this study is to assess whether expedited delivery of women with RFM identified as high risk on the basis of a low CPR improves neonatal outcomes. Secondary aims include childhood outcomes, maternal obstetric outcomes, and the predictive value of biomarkers for adverse outcomes. METHODS: International multicentre cluster randomised trial of women with singleton pregnancies with RFM at term, randomised to either an open or concealed arm. Only women with an estimated fetal weight ≥ 10th centile, a fetus in cephalic presentation and normal cardiotocograph are eligible and after informed consent the CPR will be measured. Expedited delivery is recommended in women with a low CPR in the open arm. Women in the concealed arm will not have their CPR results revealed and will receive routine clinical care. The intended sample size based on the primary outcome is 2160 patients. The primary outcome is a composite of: stillbirth, neonatal mortality, Apgar score < 7 at 5 min, cord pH < 7.10, emergency delivery for fetal distress, and severe neonatal morbidity. DISCUSSION: The CEPRA trial will identify whether the CPR is a good indicator for delivery in women with perceived reduced fetal movements. TRIAL REGISTRATION: Dutch trial registry (NTR), trial NL7557 . Registered 25 February 2019

An international internet survey of the experiences of 1,714 mothers with a late stillbirth: The STARS cohort study

Background: Stillbirth occurring after 28 weeks gestation affects between 1.5-4.5 per 1,000 births in high-income countries. The majority of stillbirths in this setting occur in women without risk factors. In addition, many established risk factors such as nulliparity and maternal age are not amenable to modification during pregnancy. Identification of other risk factors which could be amenable to change in pregnancy should be a priority in stillbirth prevention research. Therefore, this study aimed to utilise an online survey asking women who had a stillbirth about their pregnancy in order to identify any common symptoms and experiences. Methods: A web-based survey. Results: A total of 1,714 women who had experienced a stillbirth >3 weeks prior to enrolment completed the survey. Common experiences identified were: perception of changes in fetal movement (63 % of respondents), reports of a "gut instinct" that something was wrong (68 %), and perceived time of death occurring overnight (56 %). A quarter of participants believed that their baby's death was due to a cord issue and another 18 % indicated that they did not know the reason why their baby died. In many cases (55 %) the mother believed the cause of death was different to that told by clinicians. Conclusions: This study confirms the association between altered fetal movements and stillbirth and highlights novel associations that merit closer scrutiny including a maternal gut instinct that something was wrong. The potential importance of maternal sleep is highlighted by the finding of more than half the mothers believing their baby died during the night. This study supports the importance of listening to mothers' concerns and symptoms during pregnancy and highlights the need for thorough investigation of stillbirth and appropriate explanation being given to parents

Effect of encouraging awareness of reduced fetal movement and subsequent clinical management on pregnancy outcome: a systematic review and meta-analysis

Objective Reduced fetal movement (RFM), defined as a decrease in maternal perception of frequency or strength of fetal movements, is a common reason for presentation to maternity care. Observational studies demonstrate an association between RFM, stillbirth, and fetal growth restriction related to placental insufficiency. However, individual intervention studies have described varying results. This systematic review and meta-analysis aimed to determine whether interventions aiming to encourage awareness of reduced fetal movement and/or improve its subsequent clinical management reduce the frequency of stillbirth or other important secondary outcomes. Data sources Searches were conducted in MEDLINE, EMBASE, CINAHL, The Cochrane Library, Web of Science and Google Scholar. Guidelines, trial registries, and grey literature were also searched. Databases were searched from inception to the 20th January 2022. Study eligibility criteria Randomised controlled trials (RCTs) and controlled non-randomised studies (NRS) were eligible if they assessed interventions aiming to encourage awareness of fetal movement or fetal movement counting and/or improve the subsequent clinical management of RFM. Eligible populations were singleton pregnancies after 24 completed weeks of gestation. The primary review outcome was stillbirth; a number of secondary maternal and neonatal outcomes were specified in the review. Study appraisal and synthesis methods Risk of bias was assessed using Cochrane Risk of Bias 2 and ROBINS-I for RCTs and NRS respectively. Variation due to heterogeneity was assessed using I2. Data from studies employing similar interventions was combined using random effects meta-analysis. Results 1,609 citations were identified; 190 full text papers were evaluated against the inclusion criteria, 18 studies (16 RCTs and 2 NRS) were included. The evidence is uncertain about the effect of encouraging awareness of fetal movement on stillbirth compared with standard care (two studies, n=330,084); pooled aOR 1.19 (95% CI 0.96, 1.47). Interventions for encouraging awareness of fetal movement may be associated with a reduction in NICU admissions and Apgar scores <7 at five minutes of age and may not be associated with increases in caesarean section or induction of labour. The evidence is uncertain about the effect of encouraging fetal movement counting on stillbirth compared with standard care; pooled OR 0.69 (95% CI 0.18, 2.65), data from three RCTs (n=70,584). Counting fetal movements may increase maternal fetal attachment and decrease anxiety compared with standard care. When comparing combined interventions of fetal movement awareness and subsequent clinical management with standard care (one study, n=393,857) the evidence is uncertain about the effect on stillbirth (aOR 0.86, 95% CI 0.70, 1.05). Conclusions The effect of interventions for encouraging awareness of RFM alone or in combination with subsequent clinical management on stillbirth is uncertain. Encouraging awareness of fetal movement may be associated with reduced adverse neonatal outcomes without an increase in interventions in labour. Meta-analysis is hampered by variation in interventions, outcome reporting and definitions. Individual studies are frequently underpowered to detect a reduction in severe, rare outcomes and no studies were included from high-burden settings. Studies from such settings are needed to determine whether interventions can reduce stillbirth

Parents' experiences of care offered after stillbirth: An international online survey of high and middle-income countries

BACKGROUND: Stillbirth, the death of a baby before birth, is associated with significant psychological and social consequences that can be mitigated by respectful and supportive bereavement care. The absence of high-level evidence to support the broad scope of perinatal bereavement practices means that offering a range of options identified as valued by parents has become an important indicator of care quality. This study aimed to describe bereavement care practices offered to parents across different high-income and middle-income countries. METHODS: An online survey of parents of stillborn babies was conducted between December 2014 and February 2015. Frequencies of nine practices were compared between high-income and middle-income countries. Differences in proportions of reported practices and their associated odds ratios were calculated to compare high-income and middle-income countries. RESULTS: Over three thousand parents (3041) with a self-reported stillbirth in the preceding five years from 40 countries responded. Fifteen countries had atleast 40 responses. Significant differences in the prevalence of offering nine bereavement care practices were reported by women in high-income countries (HICs) compared with women in middle-income countries (MICs). All nine practices were reported to occur significantly more frequently by women in HICs, including opportunity to see and hold their baby (OR = 4.8, 95% CI 4.0-5.9). The widespread occurrence of all nine practices was reported only for The Netherlands. CONCLUSIONS: Bereavement care after stillbirth varies between countries. Future research should look at why these differences occur, their impact on parents, and whether differences should be addressed, particularly how to support effective communication, decision-making, and follow-up care

Can risk prediction models help us individualise stillbirth prevention? A systematic review and critical appraisal of published risk models.

BACKGROUND: Stillbirth prevention is an international priority - risk prediction models could individualise care and reduce unnecessary intervention, but their use requires evaluation. OBJECTIVES: To identify risk prediction models for stillbirth, and assess their potential accuracy and clinical benefit in practice. SEARCH STRATEGY: MEDLINE, Embase, DH-DATA and AMED databases were searched from inception to June 2019 using terms relevant to stillbirth, perinatal mortality and prediction models. The search was compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. SELECTION CRITERIA: Studies developing and/or validating prediction models for risk of stillbirth developed for application during pregnancy. DATA COLLECTION AND ANALYSIS: Study screening and data extraction were conducted in duplicate, using the CHARMS checklist. Risk of bias was appraised using the PROBAST tool. RESULTS: The search identified 2751 citations. Fourteen studies reporting development of 69 models were included. Variables consistently included were: ethnicity, body mass index, uterine artery Doppler, pregnancy-associated plasma protein and placental growth factor. For almost all models there were significant concerns about risk of bias. Apparent model performance (i.e. in the development dataset) was highest in models developed for use later in pregnancy and including maternal characteristics, and ultrasound and biochemical variables, but few were internally validated and none were externally validated. CONCLUSIONS: Almost all models identified were at high risk of bias. There are first-trimester models of possible clinical benefit in early risk stratification; these require validation and clinical evaluation. There were few later pregnancy models but, if validated, these could be most relevant to individualised discussions around timing of birth. TWEETABLE ABSTRACT: Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias.The authors are collaborators in the IPPIC (International Prediction of Pregnancy Complications) stillbirth project, funded by Sands (the Stillbirth and Neonatal Death Society)