New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline

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Abstract

Background

There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates.

Methods

Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass.

Results

The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential ( Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential ( Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development.

Conclusions

This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12884-023-05842-9.

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Most cited references 52

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Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.

Barbara Stoll, Nellie I Hansen, Edward Bell … (2015)

Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.

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Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis.

Li Liu, Shefali Oza, Daniel B. Hogan … (2015)

Trend data for causes of child death are crucial to inform priorities for improving child survival by and beyond 2015. We report child mortality by cause estimates in 2000-13, and cause-specific mortality scenarios to 2030 and 2035. We estimated the distributions of causes of child mortality separately for neonates and children aged 1-59 months. To generate cause-specific mortality fractions, we included new vital registration and verbal autopsy data. We used vital registration data in countries with adequate registration systems. We applied vital registration-based multicause models for countries with low under-5 mortality but inadequate vital registration, and updated verbal autopsy-based multicause models for high mortality countries. We used updated numbers of child deaths to derive numbers of deaths by causes. We applied two scenarios to derive cause-specific mortality in 2030 and 2035. Of the 6·3 million children who died before age 5 years in 2013, 51·8% (3·257 million) died of infectious causes and 44% (2·761 million) died in the neonatal period. The three leading causes are preterm birth complications (0·965 million [15·4%, uncertainty range (UR) 9·8-24·5]; UR 0·615-1·537 million), pneumonia (0·935 million [14·9%, 13·0-16·8]; 0·817-1·057 million), and intrapartum-related complications (0·662 million [10·5%, 6·7-16·8]; 0·421-1·054 million). Reductions in pneumonia, diarrhoea, and measles collectively were responsible for half of the 3·6 million fewer deaths recorded in 2013 versus 2000. Causes with the slowest progress were congenital, preterm, neonatal sepsis, injury, and other causes. If present trends continue, 4·4 million children younger than 5 years will still die in 2030. Furthermore, sub-Saharan Africa will have 33% of the births and 60% of the deaths in 2030, compared with 25% and 50% in 2013, respectively. Our projection results provide concrete examples of how the distribution of child causes of deaths could look in 15-20 years to inform priority setting in the post-2015 era. More evidence is needed about shifts in timing, causes, and places of under-5 deaths to inform child survival agendas by and beyond 2015, to end preventable child deaths in a generation, and to count and account for every newborn and every child. Bill & Melinda Gates Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

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National, regional, and global levels and trends in neonatal mortality between 1990 and 2017, with scenario-based projections to 2030: a systematic analysis

Lucia Hug, Monica Alexander, Danzhen You … (2019)

Summary Background Reducing neonatal mortality is an essential part of the third Sustainable Development Goal (SDG), to end preventable child deaths. To achieve this aim will require an understanding of the levels of and trends in neonatal mortality. We therefore aimed to estimate the levels of and trends in neonatal mortality by use of a statistical model that can be used to assess progress in the SDG era. With these estimates of neonatal mortality between 1990 and 2017, we then aimed to assess how different targets for neonatal mortality could affect the burden of neonatal mortality from 2018 to 2030. Methods In this systematic analysis, we used nationally-representative empirical data related to neonatal mortality, including data from vital registration systems, sample registration systems, and household surveys, to estimate country-specific neonatal mortality rates (NMR; the probability of dying during the first 28 days of life) for all countries between 1990 (or the earliest year of available data) and 2017. For our analysis, we used all publicly available data on neonatal mortality from databases compiled annually by the UN Inter-agency Group for Child Mortality Estimation, which were extracted on or before July 31, 2018, for data relating to the period between 1950 and 2017. All nationally representative data were assessed. We used a Bayesian hierarchical penalised B-splines regression model, which allowed for data from different sources to be weighted differently, to account for variable biases and for the uncertainty in NMR to be assessed. The model simultaneously estimated a global association between NMR and under-5 mortality rate and country-specific and time-specific effects, which enabled us to identify countries with an NMR that was higher or lower than expected. Scenario-based projections were made at the county level by use of current levels of and trends in neonatal mortality and historic or annual rates of reduction that would be required to achieve national targets. The main outcome that we assessed was the levels of and trends in neonatal mortality and the global and regional NMRs from 1990 to 2017. Findings Between 1990 and 2017, the global NMR decreased by 51% (90% uncertainty interval [UI] 46–54), from 36·6 deaths per 1000 livebirths (35·5–37·8) in 1990, to 18·0 deaths per 1000 livebirths (17·0–19·9) in 2017. The estimated number of neonatal deaths during the same period decreased from 5·0 million (4·9 million–5·2 million) to 2·5 million (2·4 million–2·8 million). Annual NMRs vary widely across the world, but west and central Africa and south Asia had the highest NMRs in 2017. All regions have reported reductions in NMRs since 1990, and most regions accelerated progress in reducing neonatal mortality in 2000–17 versus 1990–2000. Between 2018 and 2030, we project that 27·8 million children will die in their first month of life if each country maintains its current rate of reduction in NMR. If each country achieves the SDG neonatal mortality target of 12 deaths per 1000 livebirths or fewer by 2030, we project 22·7 million cumulative neonatal deaths by 2030. More than 60 countries need to accelerate their progress to reach the neonatal mortality SDG target by 2030. Interpretation Although substantial progress has been made in reducing neonatal mortality since 1990, increased efforts to improve progress are still needed to achieve the SDG target by 2030. Accelerated improvements are most needed in the regions and countries with high NMR, particularly in sub-Saharan Africa and south Asia. Funding Bill & Melinda Gates Foundation, United States Agency for International Development.

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Author and article information

Contributors

Annie R. A. McDougall: annie.mcdougall@burnet.edu.au

Journal

Journal ID (nlm-ta): BMC Pregnancy Childbirth

Journal ID (iso-abbrev): BMC Pregnancy Childbirth

Title: BMC Pregnancy and Childbirth

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2393

Publication date (Electronic): 18 July 2023

Publication date PMC-release: 18 July 2023

Publication date Collection: 2023

Volume: 23

Electronic Location Identifier: 525

Affiliations

[1 ]GRID grid.1056.2, ISNI 0000 0001 2224 8486, Maternal, Child and Adolescent Health Program, , Burnet Institute, ; 85 Commercial Road, Melbourne, VIC 3004 Australia

[2 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Obstetrics and Gynaecology, , University of Melbourne, ; Heidelberg, Australia

[3 ]GRID grid.475421.1, Policy Cures Research, ; Sydney, Australia

[4 ]GRID grid.487357.a, Concept Foundation, ; Geneva, Switzerland

[5 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, School of Public Health and Preventive Medicine, , Monash University, ; Melbourne, Australia

Article

Publisher ID: 5842

DOI: 10.1186/s12884-023-05842-9

PMC ID: 10354994

PubMed ID: 37464260

SO-VID: 28b0ee42-61cf-4eea-99b2-4e2a47752d33

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 1 May 2023

Date accepted : 11 July 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;

Award ID: INV-023749

Award Recipient : Annie R. A. McDougall Maya Goldstein Andrew Tuttle Anne Ammerdorffer A. Metin Gülmezoglu Joshua P. Vogel

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: aspirin,celecoxib,drug development,isosorbide dinitrate,l-arginine,nicardipine,nicorandil,omega-3 fatty acid,oral progesterone,preterm labour,selenium,tocolytics,vaginal progesterone

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: aspirin, celecoxib, drug development, isosorbide dinitrate, l-arginine, nicardipine, nicorandil, omega-3 fatty acid, oral progesterone, preterm labour, selenium, tocolytics, vaginal progesterone

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline

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Abstract

Background

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Conclusions

Supplementary Information

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Bacterial vaginosis and biofilm

Most cited references 52

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.

Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis.

National, regional, and global levels and trends in neonatal mortality between 1990 and 2017, with scenario-based projections to 2030: a systematic analysis

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