Preterm labour

Overview

Preterm labour – defined as the onset of childbirth before 37 weeks of gestation – is one of the leading causes of neonatal mortality worldwide, responsible for around 900,000 neonatal deaths each year. In 2020, over 13 million preterm births occurred worldwide, with survival rates significantly lower in low-income regions: here, mortality rates can reach up to 50% for infants born at or before 32 weeks. For infants who survive, preterm birth can also lead to significant lifelong health challenges, such as cerebral palsy, learning disabilities, respiratory issues, and vision and hearing impairments. Effective prevention strategies, including improvements in maternal nutrition (which is now thought to play a prominent role in the pathology of preterm labour), better management of high-risk pregnancies, and increased access to prenatal care, are vital to reducing preterm birth rates and improving neonatal outcomes globally. There is also a need for medicines to address the underlying cause of preterm labour, and improvements to those used in treating it.

Unmet needs

Despite the substantial burden of preterm labour, current treatments rely on tocolytics (medicines that delay preterm labour by relaxing uterine contractions); but these offer limited effectiveness, often have significant side effects, and pose risks to mothers and their babies. Further research is urgently needed to understand the biological mechanisms that trigger preterm labour, which will enable the development of improved screening, diagnostic tools, and medical interventions, ultimately improving treatment and outcomes. Moreover, targeted prevention strategies for high-risk pregnancies, especially in underserved regions with limited access to healthcare, are crucial to reducing the global impact of preterm birth. Promising approaches include medicines targeting various stages of the known inflammatory cascade associated with preterm labour, such as interleukin-1 receptor (IL-1) inhibitors and cytokine suppressive anti-inflammatory drugs, and studies on preventative dietary supplements like omega-3 fatty acids and polyphenols.

Funding

Global funding for preterm labour R&D totalled $35 million in 2023. The majority of funding went to basic research ($27m, 77%), as we grapple with an emerging understanding of the complexities of the underlying causes of the condition. The remaining funding was mostly divided between drugs ($4.9m, 14%) and diagnostics ($2.4m, 7%). Funding for biologics was just $0.6m, with only $17k devoted to dietary supplement R&D – an area included in the G-FINDER scope only in relation to preterm labour and maternal iron deficiency anaemia, where there is ongoing research targeting novel products or formulations. In the case of preterm labour, the dietary supplement research mostly involves animal modelling of the potential role for the amnio acid L-arginine in preventing brain neonatal damage.

More than 90% of overall funding was provided by the US NIH: a total of $32m which included 99% of funding for drugs and 95% of basic research spending, the latter mostly focused on understanding the aetiology of preterm labour and the role of the vaginal microbiome in the early onset of labour. The NIH was also the biggest funder of diagnostics ($1.0m, 43% of the total) and biologics ($0.4m, 71%).

The EC was the second biggest contributor, providing a total of $1.0m for late-stage diagnostic funding for Fine Birth, the first non-invasive point-of-care device designed to predict the risk of preterm labour in real time.

Contributions from LMICs were minimal, with India’s ICMR and DBT providing $0.3m together, and the South African MRC contributing just $11k for basic research.

Funding for preterm labour

Product landscape & pipeline

As with other maternal health conditions, product development for preterm labour is made challenging by the complexity and multiple disease aetiologies of the condition. Approved medicines marketed for decades focus on the acute treatment of preterm labour, with limited efficacy, and some serious side effects. Among candidates in development, most medicines are still in the preclinical phase, but there are also a number of in Phase III, with a preventative focus, for example targeting the inflammatory process associated with preterm labour. Unsurprisingly, the medicines pipeline is characterised by a heavy reliance on repurposed products (63% of all medicines in use or in development), helping side-step genuine concerns over teratogenicity and long lead times for new drugs, but at the expense of genuinely innovative R&D. Marketed diagnostics for preterm labour also rely on indicators that have been used for decades, such as the ultrasound measurement of cervical length and foetal fibronectin testing – with varying degrees of success – but new approaches are in development, including new imaging technologies in late development and biomarker research, which could transform the diagnostic landscape and contribute to a better understanding of the condition.

There are currently 88 medicines with both preventive and therapeutic indications in the R&D landscape for preterm labour, including 13 already marketed drugs.

Most approved medicines are drugs that have been used for several years with limited efficacy. Nine are repurposed medicines used off-label, including progesterone, indomethacin (NSAID), nifedipine (calcium channel blocker), magnesium sulfate, and isoxsuprine (beta-adrenergic agonist). Two corticoids, dexamethasone and betamethasone, can be administered alongside tocolytics as standard of care to promote fetal lung maturation in case of preterm labour. Additionally, two beta-2-adrenergic agonists are used off-label, fenoterol and hexoprenaline, although the latter is not FDA-approved and therefore not available on the US market.

There are, however four marketed medicines that are new chemical entities approved specifically for preterm labour, although with limited efficacy and availability. This includes atosiban – an oxytocin receptor antagonist launched in 2000 in the EU with limited success (and with an FDA rejection for safety reasons). Two tocolytics officially approved for preterm labour have since seen their market authorisation reduced or withdrawn due to safety or efficacy concerns: ritodrine and makena (injectable 17-alpha-hydroxyprogesterone caproate), the latter withdrawn in 2023. Allylestrenol, a synthetic steroid with progestational activity is also no longer recommended alone for preterm labour but is still under investigation in combination with other tocolytics. Together, the medicines available for preterm labour are generally suboptimal, both in terms of efficacy and safety.

Despite 59 drugs and biologics under investigation for preterm labour, over half are still in preclinical development (36/59, 61%) reflecting a nascent understanding of the basic biology of the condition. Promising candidates which have reached late-stage development (Phase III) include the preventative probiotic lactobacilli, and seven drugs, including vasodilators, statins such as pravastatin, N-acetylcysteine (NAC), aspirin, and sildenafil citrate, currently investigated alone and in combination with nifedipine

Dietary supplements (16) present a different picture, with half of the candidates (8, 50%) in Phase III, including myo-inositol, omega-3 fatty acids, vitamins (B9, B12), minerals (calcium, magnesium) and probiotics. Most dietary supplements are investigated for prevention and administered throughout pregnancy, rather than as treatment for diagnosed preterm labour.

Overall, the medicine pipeline offers limited hope for new approaches beyond the already approved tocolytics and their limitations. While preventative approaches are reaching late-stage investigation, the majority of drugs and biologics candidates are still in very early development and the consequences of a limited understanding of the pathology are visible in the absence of medicines that would allow for acute management of preterm labour once it arises. The importance of preventative medicines in the pipeline highlights the need for better diagnostics, specifically screening tests with predictive abilities to inform preventative care.

The diagnostics landscape for preterm labour is varied and diverse, covering 65 diagnostic tests, among them 14 already marketed products.

Several avenues are being explored for predicting or diagnosing preterm labour, reflecting its multiple underlying aetiologies, including maternal, foetal and placental origins. Imaging techniques present the largest share (29, 48%) and include the widely used (adopted) ultrasound measurement of cervical length, as well as 28 additional candidates in development, either with ultrasound (23), magnetic resonance imaging (2) or other technical approaches (4), targeting cervical, placental and foetal measurements. Transvaginal ultrasound-based tests represent more than half of diagnostics in late development (five out of eight), including the FineBirth transvaginal probe.

Biomarkers are also an active area of inquiry. The widely used and recommended foetal fibronectin tests (including the FDA-approved Perilynx Analyzer) have limitations due to low specificity and low positive predictive value. Novel, more specific biomarkers under investigation include placental alpha macroglobulin 1 (Partosure test), phIGFBP1 (Actim Partus rapid test), and biomarker ratios like PreTRM (sex hormone binding globulin and insulin-like growth factor binding proteins), Premaquick (Insulin-like Growth Factor-Binding Protein and Interleukin 6), or sFlt-1/PlGF ratio-based testing. There are also nine multi-biomarker tests in development, including two which have reached late development: Mirvie’s microRNA platform and PRADA, which tests for three serum biomarkers and with ongoing testing of three additional ones.

Ten diagnostic devices are marketed or in development to monitor specific physical changes that are associated with preterm labour. Marketed devices include the rarely used intrauterine pressure catheters, the approved Pregnolia system (measuring cervical softening), Bloomlife’s Wearable Integrated System and the tocodynameter (both measuring uterine contractions). Candidates under development include four electrohysterogram/electromyogram tests to monitor uterine activity and two tests detecting cervical changes (the Sheffield Mark V electrical impedance spectroscopy device and a smart vaginal diaphragm).

Multiparametric tests present the advantage of combining several technical approaches and are often developed as clinical decision support tools to aid in the prediction of preterm labour. Two of these multiparametric tests are approved for use in diagnosing preterm labour: the QuiPP app (combining risk factors, cervical length and foetal fibronectin in cervico-vaginal fluid) and the Foetal Medicine Foundation algorithm (combining maternal characteristics and medical history). There are eight additional multiparametric tests in early development, usually combining biomarkers, imaging measurements and individual risk factors for risk prediction via algorithms.

The pipeline for preterm labour diagnostics appears diverse, but this reflects the multiple potential underlying aetiologies of preterm labour, including those of maternal, foetal and placental origins, creating multiple potential avenues for diagnosis. Overall, the field remains nascent, with 84% of diagnostic candidates still in early development, and apparent difficulties in developing the predictive tests that would allow effective preventive medical approaches.

Preterm labour pipeline

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