Inclusion of people with multiple long-term conditions in pregnancy research: patient, public and stakeholder involvement and engagement in a randomised controlled trial.

BACKGROUND: Both pregnant women and those with multiple long-term conditions are under-served groups in clinical research. Informing and improving research through patient and public involvement, including pregnant women with two or more long-term health conditions, is critical to increasing their inclusion in maternity research. Giant PANDA is a randomised controlled trial, evaluating the effect of a treatment initiation strategy with nifedipine versus labetalol on severe maternal hypertension and a composite outcome of fetal/neonatal death, or neonatal unit admission. We aimed to undertake a mixed methods study-within-a-project within the Giant PANDA trial to understand barriers and facilitators to participation, understand and optimise current representativeness of clinical trial delivery of those with multiple long-term conditions and co-create a checklist to support their inclusion in pregnancy research. METHODS: We undertook online workshops with women with lived experience and hybrid workshops with healthcare professionals who look after women with multiple long-term conditions. A site audit of Giant PANDA sites provided insights into research delivery capacity and health system set-up, and how this influences inclusion. An extension to the Giant PANDA screening log captured data on multiple long-term conditions enabling analysis of the impact of these health conditions on women's inclusion in the trial. We co-created a checklist of recommendations for those designing and recruiting to similar clinical trials. RESULTS: Five key recommendations were identified including a need to (1) involve women with multiple long-term conditions as partners in maternity research and (2) minimise barriers that stop them from taking part through (3) designing and delivering research that is flexible in time and place (4) consider research as part of care for everyone, including those with multiple long-term conditions and (5) measure and report inclusion of those with two or more health conditions in maternity research. Multiple long-term conditions were not a barrier to recruitment or randomisation in the Giant PANDA trial. CONCLUSION: Women with multiple long-term conditions would like opportunities to find out about and participate in research which accounts for their needs. Our checklist aims to support those designing and delivering maternity research to optimise inclusion of individuals with multiple-long term conditions. TRIAL REGISTRATION: Giant PANDA: EudraCT number: 2020-003410-12, ISRCTN: 12,792,616.

Pregnant women with two or more long-term health problems may be less likely to be included in research. Including them in research is important to ensure we give the best care. Giant PANDA is a study comparing two medicines (nifedipine or labetalol) to manage high blood pressure in pregnancy. As part of the study, we looked at the number of women with two or more long-term health conditions included. We talked to women with experience of two or more long-term health conditions in pregnancy, and healthcare staff who look after these women. Finally, we looked at how maternity research is set up in Giant PANDA study sites. We found that women with two or more health conditions were taking part in the Giant PANDA study. Women with two or more long-term conditions would like the choice to be included in research which considers their needs. This includes being involved in the planning and ongoing support for studies. Research needs to be part of routine care, flexible, and not time consuming to help those with two or more health conditions take part. Our findings have been used to make a checklist to help plan and support studies for women and birthing people with two or more long-term health conditions.

A treatment strategy with nifedipine versus labetalol for women with pregnancy hypertension: study protocol for a randomised controlled trial (Giant PANDA).

BACKGROUND: Approximately one in ten women have high blood pressure during pregnancy. Hypertension is associated with adverse maternal and perinatal outcomes, and as treatment improves maternal outcomes, antihypertensive treatment is recommended. Previous trials have been unable to provide a definitive answer on which antihypertensive treatment is associated with optimal maternal and neonatal outcomes and the need for robust evidence evaluating maternal and infant benefits and risks remains an important, unanswered question for research and clinical communities. METHODS: The Giant PANDA study is a pragmatic, open-label, multicentre, randomised controlled trial of a treatment initiation strategy with nifedipine (calcium channel blocker), versus labetalol (mixed alpha/beta blocker) in 2300 women with pregnancy hypertension. The primary objective is to evaluate if treatment with nifedipine compared to labetalol in women with pregnancy hypertension reduces severe maternal hypertension without increasing fetal or neonatal death or neonatal unit admission. Subgroup analyses will be undertaken by hypertension type (chronic, gestational, pre-eclampsia), diabetes (yes, no), singleton (yes, no), self-reported ethnicity (Black, all other), and gestational age at randomisation categories (11 + 0 to 19 + 6, 20 + 0 to 27 + 6, 28 + 0 to 34 + 6 weeks). A cost-effectiveness analysis using an NHS perspective will be undertaken using a cost-consequence analysis up to postnatal hospital discharge and an extrapolation exercise with a lifetime horizon conditional on the results of the cost-consequence analysis. DISCUSSION: This trial aims to address the uncertainty of which antihypertensive treatment is associated with optimal maternal and neonatal outcomes. The trial results are intended to provide definitive evidence to inform guidelines and linked, shared decision-making tools, thus influencing clinical practice. TRIAL REGISTRATION: EudraCT number: 2020-003410-12, ISRCTN: 12,792,616 registered on 18 November 2020.

Postnatal health and care following hypertensive disorders in pregnancy: a prospective cohort study (BPiPP study).

INTRODUCTION: One in 10 women have hypertensive disorders in pregnancy (HDP) and are at risk of adverse short- and long-term health outcomes, yet there is limited information on their postnatal health and care needs. This study aimed to look at postnatal physical and psychological morbidity in women with HDP, compared to women without HDP, and the postnatal care received in both groups. METHODS: Within a prospective cohort study, women with and without HDP were identified and recruited on the postnatal ward of 17 maternity units across England and invited to complete a short baseline questionnaire. At 3 months postpartum, women were sent a follow-up questionnaire, with reminders. The principal outcomes were the mean score at 3 months for the Edinburgh Postnatal Depression Scale (EPDS) and the EuroQol Group 5-dimension (EQ-5D) scale. RESULTS: One thousand eight hundred twenty-nine women agreed to participate. Of these, 1757 (96%) completed the baseline questionnaire: 769 (44%) women had HDP and 988 (56%) women did not. Despite a difference in health-related quality of life and symptoms of depression at baseline between the two groups, at 3 months postnatal, within the 653 women who completed their follow-up questionnaire (37.2% of those who completed the baseline questionnaire) there were no significant differences between the groups (median EQ-5D VAS: 85 in women with HDP, 85 in women without HDP, p = 0.99 and mean EPDS score 5.5 in women with HDP, 5.0 in women without HDP, p = 0.80). Overall levels of physical postnatal morbidity were high, with 89% reporting one or more morbidities. Approximately 9% of women were re-admitted within 3 months after birth, higher in the HDP group (13.1%) higher compared to women without HDP (5.5%; RR 2.41; 95% CI 1.44-4.05). CONCLUSION: Overall levels of physical and psychological morbidity were high in this postnatal population. Although there were increased needs of women with HDP in the immediate postnatal period (compared to other women), their health assessments were similar at 3 months. This study highlights the unmet needs of women in the postnatal period, in addition to a missed opportunity to influence future pregnancies and improve the longer-term health of women and their babies.

The PROMISES study: a mixed methods approach to explore the acceptability of salivary progesterone testing for preterm birth risk among pregnant women and trained frontline healthcare workers in rural India.

INTRODUCTION: India has an overall neonatal mortality rate of 28/1000 live births, with higher rates in rural India. Approximately 3.5 million pregnancies in India are affected by preterm birth (PTB) annually and contribute to approximately a quarter of PTBs globally. Embedded within the PROMISES study (which aims to validate a low-cost salivary progesterone test for early detection of PTB risk), we present a mixed methods explanatory sequential feasibility substudy of the salivary progesterone test. METHODS: A pretraining and post-training questionnaire to assess Accredited Social Health Activists (ASHAs) (n=201) knowledge and experience of PTB and salivary progesterone sampling was analysed using the McNemar test. Descriptive statistics for a cross-sectional survey of pregnant women (n=400) are presented in which the acceptability of this test for pregnant women is assessed. Structured interviews were undertaken with ASHAs (n=10) and pregnant women (n=9), and were analysed using thematic framework analysis to explore the barriers and facilitators influencing the use of this test in rural India. RESULTS: Before training, ASHAs' knowledge of PTB (including risk factors, causes, postnatal support and testing) was very limited. After the training programme, there was a significant improvement in the ASHAs' knowledge of PTB. All 400 women reported the salivary test was acceptable with the majority finding it easy but not quick or better than drawing blood. For the qualitative aspects of the study, analysis of interview data with ASHAs and women, our thematic framework comprised of three main areas: implementation of intervention; networks of influence and access to healthcare. Qualitative data were stratified and presented as barriers and facilitators. CONCLUSION: This study suggests support for ongoing investigations validating PTB testing using salivary progesterone in rural settings.

Setting and techniques for monitoring blood pressure during pregnancy.

BACKGROUND: Regular blood pressure (BP) measurement is crucial for the diagnosis and management of hypertensive disorders in pregnancy, such as pre-eclampsia. BP can be measured in various settings, such as conventional clinics or self-measurement at home, and with different techniques, such as using auscultatory or automated BP devices. It is important to understand the impact of different settings and techniques of BP measurement on important outcomes for pregnant women. OBJECTIVES: To assess the effects of setting and technique of BP measurement for diagnosing hypertensive disorders in pregnancy on subsequent maternal and perinatal outcomes, women's quality of life, or use of health service resources. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) on 22 April 2020, and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving pregnant women, using validated BP devices in different settings or using different techniques. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: Of the 21 identified studies, we included three, and excluded 11; seven were ongoing. Of the three included RCTs (536,607 women), one was a cluster-RCT, with a substantially higher number of participants (536,233 deliveries) than the other two trials, but did not provide data for most of our outcomes. We generally judged the included studies at low risk of bias, however, the certainty of the evidence was low, due to indirectness and imprecision. Meta-analysis was not possible because each study investigated a different comparison. None of the included studies reported our primary outcome of systolic BP greater than or equal to 150 mmHg. None of the studies reported any of these important secondary outcomes: antenatal hospital admissions, neonatal unit length of stay, or neonatal endotracheal intubation and use of mechanical ventilation. Setting of BP measurement: self-measurement versus conventional clinic measurement (one study, 154 women) There were no maternal deaths in either the self-monitoring group or the usual care group. The study did not report perinatal mortality. Self-monitoring may lead to slightly more diagnoses of pre-eclampsia compared with usual care (risk ratio (RR) 1.49, 95% confidence interval (CI) 0.87 to 2.54; 154 women; 1 study; low-certainty evidence) but the wide 95% CI is consistent with possible benefit and possible harm. Self-monitoring may have little to no effect on the likelihood of induction of labour compared with usual care (RR 1.09, 95% CI 0.82 to 1.45; 154 women; 1 study; low-certainty evidence). We are uncertain if self-monitoring BP has any effect on maternal admission to intensive care (RR 1.54, 95% CI 0.06 to 37.25; 154 women; 1 study; low-certainty evidence), stillbirth (RR 2.57, 95% CI 0.13 to 52.63; 154 women; 1 study; low-certainty evidence), neonatal death (RR 1.54, 95% CI 0.06 to 37.25; 154 women; 1 study; low-certainty evidence) or preterm birth (RR 1.15, 95% CI 0.37 to 3.55; 154 women; 1 study; low-certainty evidence), compared with usual care because the certainty of evidence is low and the 95% CI is consistent with appreciable harms and appreciable benefits. Self-monitoring may lead to slightly more neonatal unit admissions compared with usual care (RR 1.53, 95% CI 0.65 to 3.62; 154 women; 1 study; low-certainty evidence) but the wide 95% CI includes the possibility of slightly fewer admissions with self-monitoring. Technique of BP measurement: Korotkoff phase IV (K4, muffling sound) versus Korotkoff phase V (K5, disappearance of sound) to represent diastolic BP (one study, 220 women) There were no maternal deaths in either the K4 or K5 group. There may be little to no difference in the diagnosis of pre-eclampsia between using K4 or K5 for diastolic BP (RR 1.16; 95% CI 0.89 to 1.49; 1 study; 220 women; low-certainty evidence), since the wide 95% CI includes the possibility of more diagnoses with K4. We are uncertain if there is a difference in perinatal mortality between the groups because the quality of evidence is low and the 95% CI is consistent with appreciable harm and appreciable benefit (RR 1.14, 95% CI 0.16 to 7.92; 1 study, 220 women; low-certainty evidence). The trial did not report data on maternal admission to intensive care, induction of labour, stillbirth, neonatal death, preterm birth, or neonatal unit admissions. Technique of BP measurement: CRADLE intervention (CRADLE device, a semi-automated BP monitor with additional features, and an education package) versus usual care (one study, 536,233 deliveries) There may be little to no difference between the use of the CRADLE device and usual care in the number of maternal deaths (adjusted RR 0.80, 95% CI 0.30 to 2.11; 536,233 women; 1 study; low-certainty evidence), but the 95% CI is consistent with appreciable harm and appreciable benefit. The trial did not report pre-eclampsia, induction of labour, perinatal mortality, preterm birth, or neonatal unit admissions. Maternal admission to intensive care and perinatal outcomes (stillbirths and neonatal deaths) were only collected for a small proportion of the women, identified by an outcome not by baseline characteristics, thereby breaking the random allocation. Therefore, any differences between the groups could not be attributed to the intervention, and we did not extract data for these outcomes. AUTHORS' CONCLUSIONS: The benefit, if any, of self-monitoring BP in hypertensive pregnancies remains uncertain, as the evidence is limited to one feasibility study. Current practice of using K5 to measure diastolic BP is supported for women with pregnancy hypertension. The benefit, if any, of using the CRADLE device to measure BP in pregnancy remains uncertain, due to the limitations and instability of the trial study design.

CKD and Pregnancy Outcomes in Africa: A Narrative Review.

Chronic kidney disease (CKD) is associated with adverse maternal and fetal outcomes and is reported to affect up to 3% of women of reproductive age in high-income countries, but estimated prevalence may be as much as 50% higher in low and middle-income countries (LMICs). All pregnancy complications occur much more frequently in women in LMICs compared with those in high-income countries. Given the anticipated high prevalence of CKD in women of reproductive age and high rates of maternal and fetal adverse events in Africa, we sought to explore the association between CKD and pregnancy outcomes in this setting through a narrative review of the literature. This review demonstrates the paucity of data in this area and highlights the systemic barriers that exist in many African countries that prevent robust management of noncommunicable diseases such as CKD during a woman's reproductive life. This evidence gap highlights the need for further research, starting by sampling normal ranges of serum creatinine concentrations in pregnant and nonpregnant women of reproductive age in the diverse populations of Africa, estimating prevalence of CKD, and understanding associated pregnancy outcomes. Research should then focus on pragmatic interventions that may improve outcomes for women and their infants.

Estimating Particulate Exposure from Modern Municipal Waste Incinerators in Great Britain.

Municipal Waste Incineration (MWI) is regulated through the European Union Directive on Industrial Emissions (IED), but there is ongoing public concern regarding potential hazards to health. Using dispersion modeling, we estimated spatial variability in PM10 concentrations arising from MWIs at postcodes (average 12 households) within 10 km of MWIs in Great Britain (GB) in 2003-2010. We also investigated change points in PM10 emissions in relation to introduction of EU Waste Incineration Directive (EU-WID) (subsequently transposed into IED) and correlations of PM10 with SO2, NOx, heavy metals, polychlorinated dibenzo-p-dioxins/furan (PCDD/F), polycyclic aromatic hydrocarbon (PAH) and polychlorinated biphenyl (PCB) emissions. Yearly average modeled PM10 concentrations were 1.00 × 10-5 to 5.53 × 10-2 µg m-3, a small contribution to ambient background levels which were typically 6.59-2.68 × 101 µg m-3, 3-5 orders of magnitude higher. While low, concentration surfaces are likely to represent a spatial proxy of other relevant pollutants. There were statistically significant correlations between PM10 and heavy metal compounds (other heavy metals (r = 0.43, p = <0.001)), PAHs (r = 0.20, p = 0.050), and PCBs (r = 0.19, p = 0.022). No clear change points were detected following EU-WID implementation, possibly as incinerators were operating to EU-WID standards before the implementation date. Results will be used in an epidemiological analysis examining potential associations between MWIs and health outcomes.

Emerging and legacy flame retardants in UK human milk and food suggest slow response to restrictions on use of PBDEs and HBCDD.

The legacy flame retardants (LFRs) polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), together with six emerging flame retardants (EFRs) were measured in United Kingdom (UK) human milk collected in 2010 (n=25) and 2014-15 (n=10). These data are the first report of the presence of EFRs in UK human milk. The most abundant EFR was ß-tetrabromoethylcyclohexane (DBE-DBCH) (average=2.5ng/g lw; geometric mean=1.5ng/g lw), which is comparable to the concentrations of the most abundant LFRs i.e. BDE 47 and α-HBCDD at 2.8 and 2.1ng/g lw, respectively (geometric mean=2.1 and 1.7). The estimated median dietary intake of ΣEFRs by UK nursing infants was 18ng/kg bw/day. EFRs were also measured in UK foodstuffs with ß-DBE-DBCH again the predominant compound detected, accounting - on average - for 64.5±23.4% of ΣEFRs. Average estimated dietary intakes of ∑EFRs in the UK were 89 and 26ng/day (1.3 and 2.6ng/body weight/day) for adults and toddlers, respectively. Concentrations of Σtri-hexa BDEs in our UK food samples exceeded those reported in UK samples from the same food categories collected in 2003-04 and 2006. Despite this and our recent report elsewhere of significant temporal declines in concentrations of BDE 209 in UK indoor dust (p<0.05) and HBCDDs in UK indoor dust and air (p<0.001), no significant temporal differences (p>0.05) were observed between concentrations of Σtri-hexa BDEs, BDE 209 and HBCDDs in human milk sampled in 2010 and those obtained in 2014-15. UK adult body burdens for EFRs were predicted via inhalation, diet and dust ingestion using a simple pharmacokinetic model. The predicted EFR body burdens compared well with observed concentrations in human milk.

Routinely collected English birth data sets: comparisons and recommendations for reproductive epidemiology.

BACKGROUND: In England there are four national routinely collected data sets on births: Office for National Statistics (ONS) births based on birth registrations; Hospital Episode Statistics (HES) deliveries (mothers' information); HES births (babies' information); and NHS Numbers for Babies (NN4B) based on ONS births plus gestational age and ethnicity information. This study describes and compares these data, with the aim of recommending the most appropriate data set(s) for use in epidemiological research and surveillance. METHODS: We assessed the completeness and quality of the data sets in relation to use in epidemiological research and surveillance and produced detailed descriptive statistics on common reproductive outcomes for each data set including temporal and spatial trends. RESULTS: ONS births is a high quality complete data set but lacks interpretive and clinical information. HES deliveries showed good agreement with ONS births but HES births showed larger amounts of missing or unavailable data. Both HES data sets had improved quality from 2003 onwards, but showed some local spatial variability. NN4B showed excellent agreement with ONS and HES deliveries for the years available (2006-2010). Annual number of births increased by 17.6% comparing 2002 with 2010 (ONS births). Approximately 6% of births were of low birth weight (2.6% term low birth weight) and 0.5% were stillbirths. CONCLUSIONS: Routinely collected data on births provide a valuable resource for researchers. ONS and NN4B offer the most complete and accurate record of births. Where more detailed clinical information is required, HES deliveries offers a high quality data set that captures the majority of English births.

Waste incineration and adverse birth and neonatal outcomes: a systematic review.

BACKGROUND: Public concern about potential health risks associated with incineration has prompted studies to investigate the relationship between incineration and risk of cancer, and more recently, birth outcomes. We conducted a systematic review of epidemiologic studies evaluating the relationship between waste incineration and the risk of adverse birth and neonatal outcomes. METHODS: Literature searches were performed within the MEDLINE database, through PubMed and Ovid interfaces, for the search terms; incineration, birth, reproduction, neonatal, congenital anomalies and all related terms. Here we discuss and critically evaluate the findings of these studies. RESULTS: A comprehensive literature search yielded fourteen studies, encompassing a range of outcomes (including congenital anomalies, birth weight, twinning, stillbirths, sex ratio and infant death), exposure assessment methods and study designs. For congenital anomalies most studies reported no association with proximity to or emissions from waste incinerators and "all anomalies", but weak associations for neural tube and heart defects and stronger associations with facial clefts and urinary tract defects. There is limited evidence for an association between incineration and twinning and no evidence of an association with birth weight, stillbirths or sex ratio, but this may reflect the sparsity of studies exploring these outcomes. CONCLUSIONS: The current evidence-base is inconclusive and often limited by problems of exposure assessment, possible residual confounding, lack of statistical power with variability in study design and outcomes. However, we identified a number of higher quality studies reporting significant positive relationships with broad groups of congenital anomalies, warranting further investigation. Future studies should address the identified limitations in order to help improve our understanding of any potential adverse birth outcomes associated with incineration, particularly focussing on broad groups of anomalies, to inform risk assessment and waste policy.

Comparative assessment of particulate air pollution exposure from municipal solid waste incinerator emissions.

BACKGROUND: Research to date on health effects associated with incineration has found limited evidence of health risks, but many previous studies have been constrained by poor exposure assessment. This paper provides a comparative assessment of atmospheric dispersion modelling and distance from source (a commonly used proxy for exposure) as exposure assessment methods for pollutants released from incinerators. METHODS: Distance from source and the atmospheric dispersion model ADMS-Urban were used to characterise ambient exposures to particulates from two municipal solid waste incinerators (MSWIs) in the UK. Additionally an exploration of the sensitivity of the dispersion model simulations to input parameters was performed. RESULTS: The model output indicated extremely low ground level concentrations of PM10, with maximum concentrations of <0.01 µ g/m(3). Proximity and modelled PM10 concentrations for both MSWIs at postcode level were highly correlated when using continuous measures (Spearman correlation coefficients ~ 0.7) but showed poor agreement for categorical measures (deciles or quintiles, Cohen's kappa coefficients ≤ 0.5). CONCLUSION: To provide the most appropriate estimate of ambient exposure from MSWIs, it is essential that incinerator characteristics, magnitude of emissions, and surrounding meteorological and topographical conditions are considered. Reducing exposure misclassification is particularly important in environmental epidemiology to aid detection of low-level risks.

Photochemical induced changes of in vitro estrogenic activity of steroid hormones.

Steroid estrogens are endocrine disrupting contaminants frequently detected in natural waters. Because these estrogens can elicit significant biological responses in aquatic organisms, it is important to study their rates and pathways of degradation in natural waters and to identify whether the transformation products retain biological activity. Photochemical kinetics experiments were conducted under simulated solar light for the hormones 17ß-estradiol (E2), 17α-ethinylestradiol (EE2), estrone (E1), equilin (EQ), and equilenin (EQN) under direct and indirect photolysis conditions. All of these hormones were susceptible to direct photodegradation, with half-lives ranging from 40 min for E1 to about 8 h for E2 and EE2. Indirect photolysis experiments with added Suwannee River fulvic acid (SRFA) lead to faster degradation rates for E2, EE2, and EQ. Added SRFA caused slower photodegradation rates for E1 and EQN, indicating that it acts primarily as an inner filter for these analytes. The well-established yeast estrogen screen (YES) was used to measure the estrogenicity of the analytes and their photoproducts. Results of YES assay experiments show that only the direct photolysis of E1 gave estrogenic products. Lumiestrone, the major E1 direct photolysis product, was isolated and characterized. It formed in 53% yield and exhibited moderate estrogenic activity. When photolysed in the presence of perinaphthenone, a potent synthetic sensitizer, E1 degraded via an indirect photolysis pathway and did not produce lumiestrone or any other active products. These results suggest that under typical natural water conditions photochemical reactions of E2, EE2, EQ, and EQN are expected to produce inactive products while E1 will give the estrogenic product lumiestrone in moderate yield.