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Factors influencing appropriate use of interventions for management of women experiencing preterm birth: A mixed-methods systematic review and narrative synthesis [1]

['Rana Islamiah Zahroh', 'Gender', 'Women S Health', 'Centre For Health Equity', 'School Of Population', 'Global Health', 'The University Of Melbourne', 'Carlton', 'Alya Hazfiarini', 'Katherine E. Eddy']

Date: 2022-08 

Abstract Background Preterm birth-related complications are the leading cause of death in newborns and children under 5. Health outcomes of preterm newborns can be improved with appropriate use of antenatal corticosteroids (ACSs) to promote fetal lung maturity, tocolytics to delay birth, magnesium sulphate for fetal neuroprotection, and antibiotics for preterm prelabour rupture of membranes. However, there are wide disparities in the rate and consistency in the use of these interventions across settings, which may underlie the differential health outcomes among preterm newborns. We aimed to assess factors (barriers and facilitators) affecting the appropriate use of ACS, tocolytics, magnesium sulphate, and antibiotics to improve preterm birth management. Methods and findings We conducted a mixed-methods systematic review including primary qualitative, quantitative, and mixed-methods studies. We searched MEDLINE, EMBASE, CINAHL, Global Health, and grey literature from inception to 16 May 2022. Eligible studies explored perspectives of women, partners, or community members who experienced preterm birth or were at risk of preterm birth and/or received any of the 4 interventions, health workers providing maternity and newborn care, and other stakeholders involved in maternal care (e.g., facility managers, policymakers). We used an iterative narrative synthesis approach to analysis, assessed methodological limitations using the Mixed Methods Appraisal Tool, and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. Behaviour change models (Theoretical Domains Framework; Capability, Opportunity, and Motivation (COM-B)) were used to map barriers and facilitators affecting appropriate use of these interventions. We included 46 studies from 32 countries, describing factors affecting use of ACS (32/46 studies), tocolytics (13/46 studies), magnesium sulphate (9/46 studies), and antibiotics (5/46 studies). We identified a range of barriers influencing appropriate use of the 4 interventions globally, which include the following: inaccurate gestational age assessment, inconsistent guidelines, varied knowledge, perceived risks and benefits, perceived uncertainties and constraints in administration, confusion around prescribing and administering authority, and inadequate stock, human resources, and labour and newborn care. Women reported hesitancy in accepting interventions, as they typically learned about them during emergencies. Most included studies were from high-income countries (37/46 studies), which may affect the transferability of these findings to low- or middle-income settings. Conclusions In this study, we identified critical factors affecting implementation of 4 interventions to improve preterm birth management globally. Policymakers and implementers can consider these barriers and facilitators when formulating policies and planning implementation or scale-up of these interventions. Study findings can inform clinical preterm birth guidelines and implementation to ensure that barriers are addressed, and enablers are reinforced to ensure these interventions are widely available and appropriately used globally.

Author summary Why was this study done? Complications from preterm birth are the leading cause of death among newborns and children under age 5.

There are 4 interventions (antenatal corticosteroids, magnesium sulphate, tocolytics, and antibiotics) that can improve health outcomes for preterm newborns, but these interventions are not used correctly or consistently across settings.

In our research, we explored how and why these 4 interventions are used or not used, in order to help other healthcare providers and families better use them in the future. What did the researchers do and find? We conducted a systematic review, which means we collected and analysed all relevant research studies about what factors (such as barriers or facilitators) might influence whether or not these 4 interventions are used.

We found 46 studies, mostly from high-income countries (37 studies), and from the perspectives of women and/or their families (5 studies), healthcare providers (38 studies), or both women and healthcare providers (3 studies).

We identified several barriers to appropriate use of the 4 interventions, starting with challenges around accurately assessing gestational age, inconsistent clinical guidelines and protocols, healthcare providers’ variable knowledge of intervention benefits and harms, and system-level challenges around stock-outs of medicine, limited human resources, and substandard labour and newborn care. What do these findings mean? Most preterm birth–related deaths happen in low- or middle-income countries (LMICs), but most of the studies we found were from high-income countries, which means that we need to be cautious in applying these findings to LMICs.

Policymakers and researchers can use these findings when developing policies and planning for scaling up of these interventions, in order to ensure equitable distribution and appropriate use of the interventions globally.

Citation: Zahroh RI, Hazfiarini A, Eddy KE, Vogel JP, Tunçalp Ӧ, Minckas N, et al. (2022) Factors influencing appropriate use of interventions for management of women experiencing preterm birth: A mixed-methods systematic review and narrative synthesis. PLoS Med 19(8): e1004074. https://doi.org/10.1371/journal.pmed.1004074 Academic Editor: Sarah J. Stock, The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, UNITED KINGDOM Received: December 14, 2021; Accepted: July 12, 2022; Published: August 23, 2022 Copyright: © 2022 Zahroh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: This research was made possible by the support of the Bill and Melinda Gates Foundation (Grant number: INV-005390) (OTO, JPV) and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a co-sponsored programme executed by the World Health Organization (WHO), and the WHO Department of Maternal, Newborn, Child, Adolescent Health and Ageing (MAB). MAB’s time is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200100264) and a Dame Kate Campbell Fellowship (University of Melbourne Faculty of Medicine, Dentistry and Health Sciences). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: ACS, antenatal corticosteroid; BEmONC, basic emergency obstetric and newborn care; CEmONC, comprehensive emergency obstetric and newborn care; COM-B, Capability, Opportunity, and Motivation Behaviour model; GBS, Group B Streptococcal Disease; LMIC, low- and middle-income country; MMAT, Mixed Methods Appraisal Tool; PPROM, preterm prelabour rupture of membranes; TDF, Theoretical Domains Framework; WHO, World Health Organisation

Introduction Preterm birth, defined as a birth before 37 weeks gestational age [1], is the leading cause of neonatal mortality worldwide [2]. Nearly 15 million babies are born prematurely every year, accounting for 10.6% of live births worldwide [2]. Importantly, more than 80% of preterm births occur in low- and middle-income countries (LMICs) [2]. There are 4 critical interventions for management of women at risk of preterm birth: antenatal corticosteroids (ACSs), tocolytics, magnesium sulphate, and antibiotics. ACS is the cornerstone intervention, effective in improving preterm birth outcomes by accelerating fetal lung maturation [3–6]. A Cochrane review concluded that when women who are at risk of preterm birth prior to 34 weeks gestation receive ACS, there is a significant reduction in risk of perinatal death, neonatal death, and respiratory distress syndrome, as well as reductions in risk of necrotising enterocolitis, intraventricular haemorrhage, and childhood developmental delays [7]. In addition, tocolytics were historically used to delay the time of birth in the hope of improving preterm birth outcomes. Studies have reported that several tocolytic agents (e.g., betamimetics and calcium channel blockers) reduced imminent preterm birth within 48 hours and 7 days of starting treatment [8,9]. However, uncertainties remain about the benefits of tocolytics, especially in terms of reducing perinatal mortality. Furthermore, magnesium sulphate can be administered to women at risk of early preterm birth for fetal neuroprotection. A Cochrane review found that the risk of babies having gross motor dysfunction and cerebral palsy are significantly reduced in women who received magnesium sulphate [10]. Lastly, antibiotic administration in women with preterm prelabour rupture of membranes (PPROM) is associated with significant reduction in maternal infection [11]. The benefits are also observed in newborns, who have reduced risks of infection, cerebral abnormality, and fewer days in special care [11]. While there are other primary interventions (e.g., smoking cessation programmes) and secondary interventions (e.g., cervical cerclage, progestational agents) for preterm birth, the 2015 World Health Organisation (WHO) recommendations on interventions to improve preterm birth outcomes specifies that the most beneficial set of maternal interventions are those aiming to improve outcomes for preterm babies when preterm birth is inevitable (e.g., ACS, magnesium sulphate, antibiotics) [12]. Due to these perinatal advantages, many international guidelines recommend ACS administration to women at risk of imminent preterm birth between 24 to 34 weeks gestational age [12–17], magnesium sulphate administration to women between 24 to 35 weeks gestational age [12,18,19], and antibiotics use for women with PPROM [12,20,21]. Tocolytics are generally not recommended for women with imminent risk of preterm birth for the purpose of improving outcomes, however may be used to facilitate ACS administration coverage or referral if needed [12,14,17]. Even though the potential benefits of these interventions to improve outcomes for preterm infants is well recognised, their use at scale varies widely across contexts and settings. These 4 interventions are highly specialised interventions that require certain diagnostic and treatment criteria for eligible women, and specific enabling environments to achieve the desired benefits and minimise harms. Identifying the necessary factors to safely deliver these interventions is critical to achieve effective scale-up for maximal impact at the country level. Previous research has documented potential facilitators and barriers to the use of ACS, tocolytics, and magnesium sulphate [22–24]. However, a critical gap is to understand how these barriers and facilitators can be used in promoting appropriate use and safe scale-up of these 4 interventions globally. To address this gap, we conducted a global mixed-methods systematic review of factors affecting appropriate use of ACS, magnesium sulphate, tocolytics, and antibiotics for PPROM to improve preterm birth outcomes. The specific objectives are to (1) explore perceptions, preferences, and experiences of women, partners, health providers, and other relevant stakeholders on the use of 4 interventions for preterm birth management; (2) explore how health workers identify women at risk of preterm birth, including assessment of gestational age, identifying signs of maternal infection, and recognising risk of preterm birth; (3) identify factors affecting administration and duration of exposure of the 4 interventions; (4) explore whether the factors affecting appropriate use differ across types of health facilities; and (5) use Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation (COM-B) models of behaviour change [25,26] to explore potential strategies in improving appropriate use and scale-up of the 4 interventions.

Discussion Our review demonstrates the complexity of factors influencing the use of ACS, tocolytics, magnesium sulphate, and antibiotics for PPROM globally. We found 46 studies, mostly from high- and middle-income countries and mostly from health providers’ perspectives. Limited availability of ultrasound gestational age dating, mixed knowledge about the effectiveness and safety of the interventions, and wrong beliefs about optimal gestational age for administration are critical barriers. Across contexts, wide variability in guidelines exists in terms of what constitutes imminence of preterm birth, gestational age criteria, maternal infections that contraindicate use, competency and authority regulated for prescription and administration, and enabling environments for administration. The inherently unpredictable nature of spontaneous preterm birth and complexity in administering these interventions complicates decision-making and implementation. Health system challenges further complicate appropriate use, such as maintenance of adequate stock, appropriate human resources for ultrasound dating, prescription and administration of interventions, and inconsistencies in availability, quality, and content of preterm labour and newborn care environments. Women also reported hesitancy in utilising interventions as they mostly learned about it during an emergency. Despite these challenges, appropriate education for health providers and women, reminder systems, audit and feedback, change champions, and multidisciplinary teamwork may be critical levers to promote appropriate use. Accurate gestational age assessment using ultrasound dating is critical in supporting time-sensitive interventions for preterm birth management. WHO recommends early ultrasound dating before 24 weeks gestational age to detect potential pregnancy complications and improve women’s pregnancy experiences [83]. However, our review shows that ultrasound dating is relatively scarce in LMICs [78], and inaccurate methods are still used, such as last menstrual period, fundal height, and timing of first antenatal visit [68,80,81]. Many community workers are unaware on the role of ultrasound dating in pregnancy [68,80,81], and ultrasound machines may only be available at higher level hospitals, which may hinder appropriate use of the interventions [78]. Programme implementers should ensure that low-resource settings have the resources and skills to provide ultrasound dating before implementing preterm birth interventions to ensure safety and minimise harm. Innovations in ultrasound technology such as handheld or portable ultrasound devices have been developed and may be particularly useful to improve and scale up basic ultrasound services in LMIC settings. Provider knowledge about the interventions was a facilitator to use; however, we observed variable knowledge and beliefs about optimal gestational age and specific populations of women in which interventions can be administered, which served as barriers to use. Variable knowledge and beliefs may reflect inconsistencies in the content of guidelines disseminated regarding these interventions. For example, administration of magnesium sulphate is recommended to be administered to eligible women before 32 weeks gestational age by WHO [12], but this gestational age ranges from 24 to 29+6 weeks in guidelines issued by UK National Institute for Health and Care Excellence [18]. Furthermore, some guidelines lack critical information, such as range of recommended gestational age, prescribing authority or contraindications of ACS use when infection is present [79]. Guideline variation is in part due to the limited evidence base for several important questions regarding populations and optimal timing of administration. More work is needed to ensure detailed, clear, and consistent information about interventions is present in national guidelines and facility-level clinical protocols and to ensure that this guidance is actively disseminated. Women’s acceptability to the interventions are also critical to address barriers of implementation. Many clinical interventions often unintentionally leave women to be part of the narrative in ensuring use, yet results of this review shows that women often feel hesitate in using the interventions as they are unfamiliar about the interventions and that they mostly learn about the it during emergency situations [23,40,51,62,66,67,80]. In practice, women may not be educated about preterm birth unless and until they are at high risk, hence why women who have experienced preterm birth in a previous pregnancy report better knowledge and feeling more confident in decision-making [51]. The TDF and COM-B mapping in our review can be used by researchers and programme implementers to inform the development of implementation models for optimal use of preterm birth management interventions in LMIC settings. Assessing the extent to which the barriers and facilitators identified in our review are potential implementation challenges in different settings is a useful starting point for formative research to scale up these preterm birth management interventions. Table 4 presents a list of questions derived from our findings and may help programme managers, policymakers, researchers, and other key stakeholders to identify and address factors that may affect implementation and scale-up of ACS, tocolytics, magnesium sulphate for fetal neuroprotection, and antibiotics for PPROM. PPT PowerPoint slide

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TIFF original image Download: Table 4. Implications for practice. This table presents a list of questions derived from our findings and may help programme managers, policymakers, researchers, and other key stakeholders to identify and address factors that may affect implementation and scale-up of ACS, tocolytics, magnesium sulphate for fetal neuroprotection, and antibiotics for PPROM. Assessing the extent to which the barriers and facilitators identified in our review are potential implementation challenges in different settings is a useful starting point for formative research to scale up these preterm birth management interventions. https://doi.org/10.1371/journal.pmed.1004074.t004 Most included studies were from high-income countries, which may affect the transferability of these findings to LMIC settings. We did not observe substantial differences between studies coming from different country income levels, thus we did not expect there would be much difference in the views of health providers’ and women in LMICs. However, this limitation highlights the importance of primary formative research and evaluation in LMICs about implementation and scale-up of preterm birth management. More work is urgently needed to implement these 4 interventions for preterm birth management in LMIC settings, where 80% of global preterm births occur, and to evaluate implementation strategies to share learnings across contexts [2]. The scope of our review meant that we did not include studies that aimed to promote early antenatal care or birth in health facilities, or optimising care for the woman and newborn in the postpartum period. Understanding interventions during these periods is critical to improve early identification of threatened preterm birth and improve care of small or sick newborns. Lastly, ACS effectiveness and safety in LMIC settings has only just been confirmed with the WHO ACTION-1 trial published in 2020 [84,85]; therefore, the impact of more recent evidence may not have been reflected in the studies included in this review. Despite these limitations, to the best of our knowledge, this is the first systematic review aiming to understand factors affecting implementation of key preterm birth management interventions globally: ACS, tocolytics, magnesium sulphate for neuroprotection, and antibiotics for PPROM. Including 4 preterm birth management interventions allowed for opportunity to explore the interconnection of preterm birth management plans, rather than focusing on single interventions. The mixed-methods approach also ensures that we have an in-depth understanding of the factors of intervention use across different type of evidence. Using TDF and COM-B behaviour change frameworks enabled us to identify critical levers and implementation challenges that could be addressed to optimise future implementation of these interventions, including in LMIC settings. Policymakers, researchers, and implementers should consider these facilitators, barriers, and potential strategies when formulating policies and planning the implementation or scale-up of these interventions.

Acknowledgments We extend our thanks to Anayda Portela (Department of Maternal, Newborn, Child and Adolescent Health, World Health Organisation) for her valuable input into the review protocol and initial analysis, Jim Berryman (Brownless Medical Library, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne) for defining and implementing the search strategy, and Weilong Cheng (Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne) in screening and translating of studies published in Mandarin. The contents of this publication are the responsibility of the authors and do not reflect the views of the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), World Health Organisation.

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