Repeat Placental Growth Factor-Based Testing in Women With Suspected Preterm Preeclampsia: A Stratified Analysis of the PARROT-2 Trial.

BACKGROUND: PlGF (placental growth factor)-based testing reduces severe maternal adverse outcomes. Repeat PlGF-based testing is not associated with improved perinatal or maternal outcomes. This planned secondary analysis aimed to determine whether there is a subgroup of women who benefit from repeat testing. METHODS: Pregnant individuals with suspected preterm preeclampsia were randomized to repeat revealed PlGF-based testing, compared with usual care where testing was concealed. Perinatal and maternal outcomes were stratified by trial group, by initial PlGF-based test result, and by PlGF-based test type (PlGF or sFlt-1 [soluble fms-like tyrosine kinase-1]/PlGF ratio). RESULTS: A total of 1252 pregnant individuals were included. Abnormal initial PlGF-based test identified a more severe phenotype of preeclampsia, at increased risk of adverse maternal and perinatal outcomes. Repeat testing was not significantly associated with clinical benefit in women with abnormal initial results. Of women with a normal initial result, 20% developed preeclampsia, with the majority at least 3 to 4 weeks after initial presentation. Repeat test results were more likely to change from normal to abnormal in symptomatic women (112/415; 27%) compared with asymptomatic women (163/890; 18%). A higher proportion of symptomatic women who changed from normal to abnormal were diagnosed with preeclampsia, compared with asymptomatic women. CONCLUSIONS: Our results do not demonstrate evidence of the clinical benefit of repeating PlGF-based testing if the initial result is abnormal. Judicious use of repeat PlGF-based testing to stratify risk may be considered at least 2 weeks after a normal initial test result, particularly in women who have symptoms or signs of preeclampsia. REGISTRATION: URL: XXX; Unique identifier: ISRCTN85912420.

Repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia (PARROT-2): a multicentre, parallel-group, superiority, randomised controlled trial.

BACKGROUND: Placental growth factor (PlGF)-based testing has high diagnostic accuracy for predicting pre-eclampsia needing delivery, significantly reducing time to diagnosis and severe maternal adverse outcomes. The clinical benefit of repeat PlGF-based testing is unclear. We aimed to determine whether repeat PlGF-based testing (using a clinical management algorithm and nationally recommended thresholds) reduces adverse perinatal outcomes in pregnant individuals with suspected preterm pre-eclampsia. METHODS: In this multicentre, parallel-group, superiority, randomised controlled trial, done in 22 maternity units across England, Scotland, and Wales, we recruited women aged 18 years or older with suspected pre-eclampsia between 22 weeks and 0 days of gestation and 35 weeks and 6 days of gestation. Women were randomly assigned (1:1) to revealed repeat PlGF-based testing or concealed repeat testing with usual care. The intervention was not masked to women or partners, or clinicians or data collectors, due to the nature of the trial. The trial statistician was masked to intervention allocation. The primary outcome was a perinatal composite of stillbirth, early neonatal death, or neonatal unit admission. The primary analysis was by the intention-to-treat principle, with a per-protocol analysis restricted to women managed according to their allocation group. The trial was prospectively registered with the ISRCTN registry, ISRCTN 85912420. FINDINGS: Between Dec 17, 2019, and Sept 30, 2022, 1253 pregnant women were recruited and randomly assigned treatment; one patient was excluded due to randomisation error. 625 women were allocated to revealed repeat PlGF-based testing and 627 women were allocated to usual care with concealed repeat PlGF-based testing (mean age 32·3 [SD 5·7] years; 879 [70%] white). One woman in the concealed repeat PlGF-based testing group was lost to follow-up. There was no significant difference in the primary perinatal composite outcome between the revealed repeat PlGF-based testing group (195 [31·2%]) of 625 women) compared with the concealed repeat PlGF-based testing group (174 [27·8%] of 626 women; relative risk 1·21 [95% CI 0·95-1·33]; p=0·18). The results from the per-protocol analysis were similar. There were four serious adverse events in the revealed repeat PlGF-based testing group and six in the concealed repeat PlGF-based testing group; all serious adverse events were deemed unrelated to the intervention by the site principal investigators and chief investigator. INTERPRETATION: Repeat PlGF-based testing in pregnant women with suspected pre-eclampsia was not associated with improved perinatal outcomes. In a high-income setting with a low prevalence of adverse outcomes, universal, routine repeat PlGF-based testing of all individuals with suspected pre-eclampsia is not recommended. FUNDING: Tommy's Charity, Jon Moulton Charitable Trust, and National Institute for Health and Care Research Guy's and St Thomas' Biomedical Research Centre.

Key outcomes for reporting in studies of pregnant women with multiple long-term conditions: a qualitative study.

BACKGROUND: Maternal multiple long-term conditions are associated with adverse outcomes for mother and child. We conducted a qualitative study to inform a core outcome set for studies of pregnant women with multiple long-term conditions. METHODS: Women with two or more pre-existing long-term physical or mental health conditions, who had been pregnant in the last five years or planning a pregnancy, their partners and health care professionals were eligible. Recruitment was through social media, patients and health care professionals' organisations and personal contacts. Participants who contacted the study team were purposively sampled for maximum variation. Three virtual focus groups were conducted from December 2021 to March 2022 in the United Kingdom: (i) health care professionals (n = 8), (ii) women with multiple long-term conditions (n = 6), and (iii) women with multiple long-term conditions (n = 6) and partners (n = 2). There was representation from women with 20 different physical health conditions and four mental health conditions; health care professionals from obstetrics, obstetric/maternal medicine, midwifery, neonatology, perinatal psychiatry, and general practice. Participants were asked what outcomes should be reported in all studies of pregnant women with multiple long-term conditions. Inductive thematic analysis was conducted. Outcomes identified in the focus groups were mapped to those identified in a systematic literature search in the core outcome set development. RESULTS: The focus groups identified 63 outcomes, including maternal (n = 43), children's (n = 16) and health care utilisation (n = 4) outcomes. Twenty-eight outcomes were new when mapped to the systematic literature search. Outcomes considered important were generally similar across stakeholder groups. Women emphasised outcomes related to care processes, such as information sharing when transitioning between health care teams and stages of pregnancy (continuity of care). Both women and partners wanted to be involved in care decisions and to feel informed of the risks to the pregnancy and baby. Health care professionals additionally prioritised non-clinical outcomes, including quality of life and financial implications for the women; and longer-term outcomes, such as children's developmental outcomes. CONCLUSIONS: The findings will inform the design of a core outcome set. Participants' experiences provided useful insights of how maternity care for pregnant women with multiple long-term conditions can be improved.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Targeted health and social care interventions for women and infants who are disproportionately impacted by health inequalities in high-income countries: a systematic review.

BACKGROUND: Disadvantaged populations (such as women from minority ethnic groups and those with social complexity) are at an increased risk of poor outcomes and experiences. Inequalities in health outcomes include preterm birth, maternal and perinatal morbidity and mortality, and poor-quality care. The impact of interventions is unclear for this population, in high-income countries (HIC). The review aimed to identify and evaluate the current evidence related to targeted health and social care service interventions in HICs which can improve health inequalities experienced by childbearing women and infants at disproportionate risk of poor outcomes and experiences. METHODS: Twelve databases searched for studies across all HICs, from any methodological design. The search concluded on 8/11/22. The inclusion criteria included interventions that targeted disadvantaged populations which provided a component of clinical care that differed from standard maternity care. RESULTS: Forty six index studies were included. Countries included Australia, Canada, Chile, Hong Kong, UK and USA. A narrative synthesis was undertaken, and results showed three intervention types: midwifery models of care, interdisciplinary care, and community-centred services. These intervention types have been delivered singularly but also in combination of each other demonstrating overlapping features. Overall, results show interventions had positive associations with primary (maternal, perinatal, and infant mortality) and secondary outcomes (experiences and satisfaction, antenatal care coverage, access to care, quality of care, mode of delivery, analgesia use in labour, preterm birth, low birth weight, breastfeeding, family planning, immunisations) however significance and impact vary. Midwifery models of care took an interpersonal and holistic approach as they focused on continuity of carer, home visiting, culturally and linguistically appropriate care and accessibility. Interdisciplinary care took a structural approach, to coordinate care for women requiring multi-agency health and social services. Community-centred services took a place-based approach with interventions that suited the need of its community and their norms. CONCLUSION: Targeted interventions exist in HICs, but these vary according to the context and infrastructure of standard maternity care. Multi-interventional approaches could enhance a targeted approach for at risk populations, in particular combining midwifery models of care with community-centred approaches, to enhance accessibility, earlier engagement, and increased attendance. TRIAL REGISTRATION: PROSPERO Registration number: CRD42020218357.

The effect of becoming a Fistula Advocate on the recovery of women with Obstetric Fistula in Sierra Leone: A qualitative study.

Engaging women affected by Obstetric Fistula as advocates has been proposed as an effective strategy to raise awareness of the condition. Limited literature exists on the experience of those who become advocates. A model of community education, in Sierra Leone, trained women affected by Obstetric Fistula to become volunteer Fistula Advocates. This study explored Advocates' perception of their role and its influence on their recovery and reintegration. This was a qualitative study, undertaken in Sierra Leone, collecting data from 7 Fistula Advocates and 3 Key Informants (with roles in either clinical or outreach care for women with Obstetric Fistula or training and supervision of Advocates), using semi-structured interviews. Data was subject to a thematic analysis and related to a conceptual framework for mental health recovery. Intrinsic factors motivating Advocates to undertake this role were influenced by psycho-social support received and the possibility for financial independence. Advocates used personal stories in their work to define a new identity, change perceptions and reduce stigma. Benefits associated with the interactions and relationships created through providing and receiving peer support were voiced. Surgical treatment was described as an important factor influencing recovery. The Advocates said economic empowerment helped recovery and reintegration, and the voluntary nature of the Advocate role limited the impact of this. Overall Advocates perceived their role positively, reporting psychological, social, and economic benefits. The complexities of recovery from Obstetric Fistula were highlighted and connections drawn between the treatment of physical symptoms, the socio-cultural context and mental health recovery. They described the role positively influencing existing relationships and initiating supportive, empowering social interactions between women affected by Obstetric Fistula and with Non-Governmental Organisation staff and community members. The study offers insights into the potential for community-based approaches to facilitate access to treatment for sensitive and stigmatising health problems and support recovery.

Maternal and child outcomes for pregnant women with pre-existing multiple long-term conditions: protocol for an observational study in the UK.

INTRODUCTION: One in five pregnant women has multiple pre-existing long-term conditions in the UK. Studies have shown that maternal multiple long-term conditions are associated with adverse outcomes. This observational study aims to compare maternal and child outcomes for pregnant women with multiple long-term conditions to those without multiple long-term conditions (0 or 1 long-term conditions). METHODS AND ANALYSIS: Pregnant women aged 15-49 years old with a conception date between 2000 and 2019 in the UK will be included with follow-up till 2019. The data source will be routine health records from all four UK nations (Clinical Practice Research Datalink (England), Secure Anonymised Information Linkage (Wales), Scotland routine health records and Northern Ireland Maternity System) and the Born in Bradford birth cohort. The exposure of two or more pre-existing, long-term physical or mental health conditions will be defined from a list of health conditions predetermined by women and clinicians. The association of maternal multiple long-term conditions with (a) antenatal, (b) peripartum, (c) postnatal and long-term and (d) mental health outcomes, for both women and their children will be examined. Outcomes of interest will be guided by a core outcome set. Comparisons will be made between pregnant women with and without multiple long-term conditions using modified Poisson and Cox regression. Generalised estimating equation will account for the clustering effect of women who had more than one pregnancy episode. Where appropriate, multiple imputation with chained equation will be used for missing data. Federated analysis will be conducted for each dataset and results will be pooled using random-effects meta-analyses. ETHICS AND DISSEMINATION: Approval has been obtained from the respective data sources in each UK nation. Study findings will be submitted for publications in peer-reviewed journals and presented at key conferences.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

Association of pregnancy complications/risk factors with the development of future long-term health conditions in women: overarching protocol for umbrella reviews.

INTRODUCTION: With good medical care, most pregnancy complications like pre-eclampsia, gestational diabetes, etc resolve after childbirth. However, pregnancy complications are known to be associated with an increased risk of new long-term health conditions for women later in life, such as cardiovascular disease. These umbrella reviews aim to summarise systematic reviews evaluating the association between pregnancy complications and five groups of long-term health conditions: autoimmune conditions, cancers, functional disorders, mental health conditions and metabolic health conditions (diabetes and hypertension). METHODS AND ANALYSIS: We will conduct searches in Medline, Embase and the Cochrane database of systematic reviews without any language restrictions. We will include systematic reviews with or without meta-analyses that studied the association between pregnancy complications and the future risk of the five groups of long-term health conditions in women. Pregnancy complications were identified from existing core outcome sets for pregnancy and after consultation with experts. Two reviewers will independently screen the articles. Data will be synthesised with both narrative and quantitative methods. Where a meta-analysis has been carried out, we will report the combined effect size from individual studies. For binary data, pooled ORs with 95% CIs will be presented. For continuous data, we will use the mean difference with 95% CIs. The findings will be presented in forest plots to assess heterogeneity. The methodological quality of the studies will be evaluated with the AMSTAR 2 tool or the Cochrane risk of bias tool. The corrected covered area method will be used to assess the impact of overlap in reviews. The findings will be used to inform the design of prediction models, which will predict the risk of women developing these five group of health conditions following a pregnancy complication. ETHICS AND DISSEMINATION: No ethical approvals required. Findings will be disseminated through publications in peer-reviewed journals and conference presentations.

Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study.

BACKGROUND: Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). STUDY DESIGN: Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. RESULTS: The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8-24.6%], 23.5% [23.0-24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8-31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04-3.17] 45-49 years vs 15-19 years), multigravid (1.68 [1.50-1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44-1.76], body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 [1.46-1.77) vs non-smoker). CONCLUSION: Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Validation of the BPro radial pulse waveform acquisition device in pregnancy and gestational hypertensive disorders.

OBJECTIVE: To validate the BPro blood pressure (BP) wrist device for use in pregnancy and preeclampsia according to the Universal Standard protocol. PARTICIPANTS AND METHODS: BP was measured sequentially in 45 pregnant women (including 15 with preeclampsia, 15 with gestational hypertension and 15 who remained normotensive) alternating between a mercury sphygmomanometer and BPro device. RESULTS: The BPro is accurate in pregnancy with a mean device-observer difference of -1.7 ± 6.1 and 0.1 ± 4.6 mmHg for SBP and DBP, respectively. In women with preeclampsia, BPro also met the validation criteria for the Universal Standard protocol with a mean device-observer difference of -2.7 ± 7.1 and 0.3 ± 4.7 mmHg for SBP and DBP, respectively. However, the number of absolute BP differences within 5 mmHg was considerably fewer in those with preeclampsia when compared to the other two subgroups. CONCLUSION: The BPro device can be recommended for BP measurement in pregnancy but should be used with caution in those with confirmed preeclampsia.

Maternal and perinatal health research priorities beyond 2015: an international survey and prioritization exercise.

BACKGROUND: Maternal mortality has declined by nearly half since 1990, but over a quarter million women still die every year of causes related to pregnancy and childbirth. Maternal-health related targets are falling short of the 2015 Millennium Development Goals and a post-2015 Development Agenda is emerging. In connection with this, setting global research priorities for the next decade is now required. METHODS: We adapted the methods of the Child Health and Nutrition Research Initiative (CHNRI) to identify and set global research priorities for maternal and perinatal health for the period 2015 to 2025. Priority research questions were received from various international stakeholders constituting a large reference group, and consolidated into a final list of research questions by a technical working group. Questions on this list were then scored by the reference working group according to five independent and equally weighted criteria. Normalized research priority scores (NRPS) were calculated, and research priority questions were ranked accordingly. RESULTS: A list of 190 priority research questions for improving maternal and perinatal health was scored by 140 stakeholders. Most priority research questions (89%) were concerned with the evaluation of implementation and delivery of existing interventions, with research subthemes frequently concerned with training and/or awareness interventions (11%), and access to interventions and/or services (14%). Twenty-one questions (11%) involved the discovery of new interventions or technologies. CONCLUSIONS: Key research priorities in maternal and perinatal health were identified. The resulting ranked list of research questions provides a valuable resource for health research investors, researchers and other stakeholders. We are hopeful that this exercise will inform the post-2015 Development Agenda and assist donors, research-policy decision makers and researchers to invest in research that will ultimately make the most significant difference in the lives of mothers and babies.