Abstract
In brief
Preterm birth is the leading cause of perinatal morbidity and mortality; however, current therapies offer limited efficacy to delay birth and improve neonatal outcomes. This review explores the potential of repurposing drugs with known safety profiles to quench uterine contractions and inflammation, identifying promising agents for clinical trials.
Abstract
Preterm birth is the leading cause of neonatal morbidity and mortality globally. Despite extensive research into the underlying pathophysiology, rates of preterm birth have not significantly reduced. Currently, preterm labour management is based on optimising neonatal outcomes. Treatment involves administering drugs (tocolytics) to suppress uterine contractions to allow sufficient time for transfer to an appropriate facility and administration of antenatal corticosteroids for fetal lung maturation. Current tocolytics are limited as they are associated with adverse maternal and fetal effects and only delay delivery for a short period. There has been a serious lack of therapeutic development for preterm birth, and new approaches to protect against or delay preterm birth are urgently needed. Repurposing drugs for the prevention of preterm birth presents as a promising approach by reducing the time and costs associated with pharmaceutical drug development. In this review, we explore the evidence for the potential of therapies, specifically proton pump inhibitors, tumour necrosis factor inhibitors, prostaglandin receptor antagonists, aspirin, and statins, to be repurposed as preventatives and/or treatments for preterm birth. Importantly, many of these innovative approaches being explored have good safety profiles in pregnancy. We also review how delivery of these drugs can be enhanced, either through targeted delivery systems or via combination therapy approaches. We aim to present innovative strategies capable of targeting multiple aspects of the complex pathophysiology that underlie preterm birth. There is an urgent unmet need for preterm birth therapeutic development, and these strategies hold great promise for improving neonatal outcomes.
Introduction
Preterm birth is defined as delivery before 37 completed weeks of gestation (World Health Organisation 2015). It is the leading cause of neonatal morbidity and mortality globally and is considered the most important determinant of poor outcomes for babies, in terms of both survival and long-term quality of life (World Health Organisation 2015). The most recent global data show that 15.22 million babies were born preterm in 2019, accounting for 0.66 million neonatal deaths (Cao et al. 2022). Despite extensive research and implementation of improved perinatal care, the overall rates of prematurity are not significantly reducing. While there was a small decline in preterm birth rates between 2019 and 2020 from 10.2% to 10.1% in the United States, the rates remain high particularly among non-Hispanic Black women where the rate was almost double compared to the rate among non-Hispanic white women (14.4% compared with 9.1%, respectively) (Hamilton et al. 2021).
The majority of preterm births occur spontaneously, without indication, but can also be initiated by the healthcare team based on medical complications of the pregnant patient, placenta, or fetus (overview in Fig. 1) (Vogel et al. 2018). Spontaneous preterm birth can be caused by cervical incompetency (premature dilation/ripening of cervix), preterm pre-labour rupture of membranes (PPROM), or spontaneous labour (Fig. 1). Cervical incompetency, characterised by a short cervix at mid-trimester (cervical length <25mm before 24 weeks), is a useful predictive marker for preterm birth risk, although it occurs at a low incidence, which limits the utility of screening (Glover & Manuck 2018). Risk factors for spontaneous preterm birth include multiple gestation, history of preterm birth, short cervix length, smoking, low socioeconomic status, and maternal age (World Health Organisation 2015, Glover & Manuck 2018). Maternal medical conditions during pregnancy such as diabetes, high blood pressure, or other pregnancy complications also increase the risk of preterm labour. Addressing modifiable risk factors can reduce the risk of preterm birth and should be implemented during care. However, it needs to be noted that many preterm births occur without these risk factors. The idiopathic nature of spontaneous preterm labour undoubtedly contributes to our resounding inability to identify pregnancies at high risk of preterm labour.
Preterm birth causes and current strategies for management. Preterm birth either can be provider initiated or can occur spontaneously. Most preterm births are spontaneous, although the rate of provider-initiated preterm birth is increasing. Provider-initiated preterm birth occurs through caesarean section or induction of labour indicated by complications associated with the pregnancy, the fetus, or the placenta. Spontaneous preterm births can be caused by cervical insufficiency, preterm pre-labour rupture of membranes (PPROM), or spontaneous preterm labour. An insufficient cervix is associated with either a short cervical length or premature ripening and dilation. Cervical insufficiency is managed surgically with cervical cerclage (stitch) or medically with vaginal progesterone to maintain uterine quiescence. PPROM is strongly associated with intrauterine infection and is treated with antibiotics to prevent further infection. Tocolysis use during PPROM is topical. Spontaneous preterm labour is often idiopathic but can be associated with intra-amniotic infection (treated with antibiotics) or caused by inflammation in the absence of detectable microbes (sterile inflammation). Preterm labour is managed by tocolysis to provide time to prepare the baby for birth. This figure was created with BioRender.com.
Citation: Reproduction 165, 1; 10.1530/REP-22-0226
Even with increased surveillance and tailored treatment for those at high risk, there is relatively little that can be done to mitigate preterm birth, in terms of not only preventing pregnancies from going into preterm labour but also delaying birth for patients in established preterm labour. In preterm labour, management is based on optimising neonatal outcomes. Tocolytics are primarily used to allow sufficient time for transfer to an appropriate tertiary facility and administration of corticosteroids for fetal lung maturation and magnesium sulphate for fetal neuroprotection. However, therapeutics that can safely prolong gestation for longer periods are urgently needed.
This review will discuss the current therapies in use for the management of preterm labour and prevention of preterm birth and will review the evidence that exists for emerging novel therapeutics. The focus will be on therapies that have a known safety profile in pregnancy and could be repurposed for their potential tocolytic properties.
Pathophysiology of preterm birth
The processes and pathways in both normal term and preterm labour are not completely understood. However, it is widely accepted that the onset of labour is characterised by the switch of the uterus from a quiescent to contractile state accompanied by a shift from anti-inflammatory to pro-inflammatory signalling. The three main components of the common pathway of parturition are (i) an increase in myometrial contractility, (ii) remodelling and ripening of the cervix, and (iii) activation and weakening of the fetal membranes and decidua (Gotsch et al. 2009). These processes occur physiologically at term labour via inflammatory processes, but preterm labour is driven by a pathological level of inflammation, with inflammatory responses occurring at a heightened magnitude (Romero et al. 2006, Gotsch et al. 2009).
The inflammatory response in term and preterm labour is characterised by the expression and release of pro-inflammatory cytokines (i.e. interleukin (IL)1B, IL6, and tumour necrosis factor (TNF)), chemokines (CXC motif chemokine ligand-8 and monocyte chemoattractant protein-1), and prostaglandin (PG) E2 and PGF2a by the myometrium and the fetal membranes and is enhanced by infiltrating leukocytes to these tissues (Sivarajasingam et al. 2016). Progesterone is key in maintaining quiescence by repressing the expression of these chemokines, cytokines, and contraction-associated proteins such as oxytocin receptors, gap junction protein connexin-43, and PG receptors (Wu & DeMayo 2017). Immune cells, particularly macrophages and T-regulatory cells, are also important in maintaining maternal–fetal immune homeostasis (Gomez-Lopez et al. 2021).
The myometrium is the muscular layer of the uterus, primarily composed of smooth muscle cells. Myometrial contractility is based on the interaction between myosin and actin in myometrial smooth muscle cells, driven by calcium-dependent myosin light-chain kinase activity (Lopez Bernal 2003). The key mediators of myometrial activation are cytokines, PGs, and oxytocin, which modulate myometrial contractions through their downstream signalling (Fig. 2 and 3). The downstream effect is increased calcium mobilisation within myometrial cells, leading to increased myometrial contractility (Gotsch et al. 2009).
Mechanisms of actions of current clinical tocolytics and repurposed therapies in reducing myometrial contractility, cervical remodelling, and rupture of membranes to suppress preterm labour. The three main components of the common pathway of parturition are (i) increase in myometrial contractility, (ii) remodelling of the cervix, and (iii) activation and rupture of the fetal membranes. These physiological events characterise the transition of the quiescent uterus to an active, contractile state, leading to term and preterm birth. They are mediated by inflammation, driven predominantly via prostaglandins, pro-inflammatory cytokines/chemokines, and leukocytes. These pro-inflammatory molecules have a multitude of effects, including recruitment and/or activation of macrophages, neutrophils, and T cells in the uterus. Cytokines and prostaglandins also act directly on the cells of the myometrium and fetal membranes. Extracellular matrix metalloproteinases (MMPs) degrade the amnion, chorion, and cervical matrix as part of cervical remodelling and weakening and rupture of fetal membranes. The established and proposed mechanisms of action of current tocolytics and repurposed therapies on the key mediators of the pathway of parturition are demonstrated. PGE2, prostaglandin E2; PGF2a, prostaglandin F2-alpha; COX-2, cyclo-oxygenase 2; TNF, tumour necrosis factor; NSAIDs, non-steroidal anti-inflammatory drugs; PPIs, proton pump inhibitors; C5a, complement component 5a; IL1R, interleukin-1 receptor; BSCI, broad-spectrum chemokine inhibitor. This figure was created with BioRender.com.
Citation: Reproduction 165, 1; 10.1530/REP-22-0226
Mechanisms of actions of current clinical tocolytics and repurposed therapies in myometrial cells. Activation of toll-like receptors (TLRs) by PAMPs or DAMPs on cells in gestational tissues or on leukocytes leads to a downstream expression of contraction-associated proteins, particularly pro-inflammatory cytokines and chemokines. The amplification of inflammatory signals ultimately increases the expression of additional contraction-associated proteins, including prostaglandins, connexin-43, and oxytocin receptors, which contribute to increased myometrial contractility. Most of the current tocolytics focus on preventing or reducing myometrial contractility, which is a process dependent on the concentration of intracellular calcium (Ca2+). This figure depicts a myometrial cell membrane and intracellular space and details the actions and targets of the current tocolytics as well as the proposed mechanisms and targets of emerging repurposed therapies in myometrial cells. DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; HO-1, heme-oxygenase-1; CO, carbon monoxide; CaM, calmodulin; MLCP, myosin light-chain phosphatase; MLCK, myosin light-chain kinase; ROCK, Rho-associated protein kinase; COX-2, cyclo-oxygenase 2; NF-kB, nuclear factor kappa B; NSAIDs, non-steroidal anti-inflammatory drugs; PPIs, proton pump inhibitors. This figure was created with BioRender.com.
Citation: Reproduction 165, 1; 10.1530/REP-22-0226
Cervix remodelling – encompassed by cervical softening, ripening, and dilation – is driven by pro-inflammatory cytokines through increased expression of matrix metalloproteinases (MMPs), cyclo-oxygenase-2 (COX-2), and PGE2, leading to softening and dilation of the cervix (Holt et al. 2011). Similarly, increases in MMPs, collagenases, and PGs and reductions in tissue MMP inhibitors result in the activation, weakening, and rupture of fetal membranes (Fig. 2). These processes are highly controlled during term labour, and investigation of how these processes may differ in preterm labour is paramount.
Infection-driven and sterile inflammation in preterm birth
Preterm birth is considered a syndrome involving multiple causal and associated aetiologies, but the most well-established cause is inflammation of the amniotic cavity known as ‘intra-amniotic inflammation’ (Romero et al. 2006, 2014, Goldenberg et al. 2008). Intra-amniotic inflammation can occur in the absence of microbes, known as sterile inflammation, or be driven by infection (chorioamnionitis). The established and novel mechanisms of the immunobiology of preterm labour and birth are detailed in a recent review by Gomez-Lopez and colleagues (Gomez-Lopez et al. 2022). Briefly, sterile inflammation is triggered when danger signals called damage-associated molecular patterns (DAMPs) activate pattern-recognition receptors in the myometrium or fetal membranes to induce an acute innate immune response. DAMPs are endogenous molecules released because of cellular necrosis, stress, or ischaemia (Nadeau-Vallee et al. 2016). This is characterised by elevated inflammatory mediators including IL6 and infiltration of leukocytes (neutrophils, monocytes, macrophages, and T cells) into gestational tissues. Intra-amniotic infections are typically associated with bacterial microorganisms ascending from the lower genital tract and are strongly associated with spontaneous preterm labour (Romero et al. 2001). Some infections can be subclinical, making it difficult to detect and diagnose (Romero et al. 2001). In cases of infection during pregnancy, pathogens are recognised by their microbial molecules called pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors such as toll-like receptors on gestational tissues and stimulate the release of pro-inflammatory chemokines and cytokines. This leads to increases in PG and MMP production which ultimately activates the parturition pathways, as described above (Romero et al. 2001). While antibiotics are used for intrauterine and systemic infections during pregnancy, they are inefficient in preventing preterm birth in cases of preterm labour with intact membranes (Olson et al. 2008), suggesting labour induced by infection arises via inflammatory pathways that cannot be slowed by treating the infection (Nadeau-Vallee et al. 2016). Therefore, specifically treating the inflammation that precedes and causes preterm birth presents as a very promising target for intervention.
Current clinical preterm birth therapeutics (tocolytics)
Tocolytics are drugs used to delay preterm delivery by relaxing uterine myometrial contractions. They are used to prolong pregnancy to provide time to administer antenatal corticosteroids to accelerate fetal lung maturation and transfer patients to a specialised neonatal unit. Both actions have been shown to reduce neonatal morbidity and mortality (Vogel et al. 2018). However, there is no strong evidence that any tocolytic improves neonatal outcomes such as respiratory distress syndrome or death (Haas et al. 2012). Tocolytics are primarily used in cases of spontaneous preterm labour. The use of tocolysis in PPROM is not completely supported due to insufficient evidence to suggest a beneficial role, and any benefits must be weighed against the potential harm associated, particularly to the fetus (Mackeen et al. 2014). Therefore, this review will focus on tocolysis for spontaneous preterm labour with intact membranes.
There are several types of tocolytics which vary in mechanism, cost, safety profile and effectiveness (Haas et al. 2012, Flenady et al. 2014a,b, Reinebrant et al. 2015). Availability varies between countries due to differences in regulatory approvals. The regulatory challenges for preterm birth therapeutic development are discussed in detail in a focused review (Coler et al. 2021).
Calcium channel blockers
Calcium channel blockers (CCBs), such as nifedipine and nicardipine, are conventionally prescribed as anti-hypertensive agents; however, they were investigated and repurposed as tocolytics in the 1980s due to their potent relaxant effect on smooth muscle contractions (Ulmsten et al. 1980). Today, due to significant challenges for development of obstetric medications, including lengthy delays in regulatory approval, these CCBs continue to be used off-label for the treatment of preterm labour. Nifedipine is often considered as the first-line tocolytic therapy for the management of spontaneous preterm labour.
CCBs are non-specific smooth muscle relaxants. They bind to L-type voltage-gated calcium channels in the myometrial cell plasma membrane and inhibit the inward flux of calcium ions required for muscle contractions (Fig. 3). Nifedipine is widely used due to its low cost, availability, favourable safety profile, and capacity for oral administration. Nicardipine has the additional advantage of both oral and i.v. administration; however, i.v. nicardipine has not been shown to be more beneficial in prolonging the duration of pregnancy in comparison to oral nifedipine (Le Ray et al. 2010).
Nifedipine has less adverse effects compared to many other tocolytics (Flenady et al. 2014b). The side effects of nifedipine, including headaches, tachycardia, anxiety, vomiting, and hypotension, are relatively well tolerated and manageable (Flenady et al. 2014b). Additionally, nifedipine does not appear to adversely affect the fetus: not altering fetal movement, heart rate, or blood flow (de Heus et al. 2009).
The latest Cochrane review on the use of CCBs (primarily nifedipine) as tocolytic therapies showed there is insufficient evidence regarding efficacy to improve perinatal mortality or rate of preterm birth (Flenady et al. 2014b). The review included 38 trials of 3550 patients; nifedipine was assessed in 35 of these trials and nicardipine in three. In the two studies that compared nifedipine to placebo or no treatment, there was a delay in delivery and a reduction in birth less than 48 h after trial entry with nifedipine use (Zhang & Liu 2002, Ara & Banu 2008). This supports the use of nifedipine to prolong pregnancies in the short term, to provide time for corticosteroid administration and to transfer to higher level care. However, in terms of the outcome of reducing the incidence of preterm birth, the two trials found conflicting results. The placebo-controlled trial showed nifedipine was no different to placebo (Ara & Banu 2008), while the non-placebo controlled trial showed nifedipine reduced the occurrence of preterm birth (Zhang & Liu 2002). These different findings may be attributable to the fundamental differences between the two trials, particularly regarding doses and blinding to the intervention. Well-designed trials with appropriate primary outcomes and blinding would be needed to truly resolve the contention, and further investigation is needed.
Of note, while nifedipine is primarily used to arrest preterm labour (acute tocolysis), it can also be used to subsequently maintain uterine quiescence (maintenance tocolysis). However, there is very limited evidence supporting the use of nifedipine for maintenance therapy (Naik Gaunekar et al. 2013, Ding et al. 2016) and therefore is not recommended. Thus, although nifedipine is often considered the standard course of treatment for preterm labour, the benefits in improving neonatal survival are minimal, and further investigation is warranted to elucidate why these therapies are limited and how we can improve the development of acute tocolytic therapies.
Oxytocin receptor antagonists
Atosiban is an i.v. medication that acts as an oxytocin receptor antagonist. Unlike other tocolytic agents, atosiban has been developed exclusively for the management of preterm labour. Despite this, it has not been approved by the United States Food and Drug Administration (FDA) but is available for clinical use in Europe.
Atosiban is a peptide analogue of oxytocin and competitively inhibits oxytocin from binding to its membrane-bound receptors in the myometrium and decidua. This prevents the signalling required for the release of intracellular calcium and thus inhibits myometrial contractions (Fig. 3). Atosiban should have limited systemic maternal effects as oxytocin receptors are only highly expressed in the uterus and myoepithelial cells in mammary glands (Fuchs et al. 1984).
As demonstrated in trials, atosiban is associated with fewer maternal adverse effects compared with other tocolytics and therefore is often the preferred tocolytic in high-resource settings but is limited in low-resource settings due to its high cost (Coler et al. 2021). Atosiban can cross the placenta to the fetus but does not have any adverse effects on fetal heart rate, fetal movement, or fetal blood flow (de Heus et al. 2009). Atosiban is currently the only oxytocin receptor antagonist used clinically. Barusiban was tested in phase II clinical trials but did not show any difference to placebo in terms of reducing uterine contractions or proportion of patients delivering within 48 h (Thornton et al. 2009). As atosiban and barusiban are peptide antagonists, their oral bioavailability is poor due to degradation and limited absorption of peptides in the gastrointestinal tract. To counter this issue, non-peptides with high oxytocin receptor selectivity such as retosiban are being investigated (Thornton et al. 2017). Three clinical trials assessing retosiban in the management of preterm birth were evaluated in a systematic review but did not show a significant advantage in prolonging pregnancies compared to placebo (Marchand et al. 2021). However, the favourable safety profile with minimal maternal and fetal adverse effects support further research into this class of drugs.
Betamimetics
Betamimetics, also known as beta-2 adrenergic receptor agonists, are a class of drugs that act on these receptors in myometrial cells. They reduce uterine contractions by binding to the beta-2 adrenergic receptors on the surface of myometrial smooth muscle cells, activating adenylyl cyclase to form cAMP (Fig. 3). In turn, elevated levels of cAMP lead to a decrease in myosin light-chain kinase activity. Therefore, the smooth muscle machinery – myosin and actin – are prevented from interacting to generate contractile force.
Betamimetics were investigated for repurposing as tocolytics in the 1960s after their development as anti-asthma medications. Terbutaline was used off-label (as with most tocolytics) under the US FDA classification of Category B (no evidence of risk in humans) until it was classified as Category C (risk cannot be ruled out) in 2011. While still used in some countries, the use of betamimetics such as terbutaline, ritodrine, and salbutamol has significantly dropped due to serious adverse maternal side effects (such as tachycardia, hyperglycaemia, and chest pain), leading to immediate withdrawal from treatment (Neilson et al. 2014). Additionally, betamimetics are not recommended for long-term tocolysis.
Betamimetics have not been shown to significantly reduce perinatal death compared with placebo (Neilson et al. 2014). While they demonstrate some efficacy in delaying delivery (Flenady et al. 2014a,b, Neilson et al. 2014), they are not often considered as a first-line therapy for preterm birth management due to serious adverse effects.
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, have also been utilised as tocolytics. NSAIDs work via inhibition of COX-1 and COX-2 (Fig. 3) (Vane 1971). COX enzymes are responsible for synthesis of PGs, and therefore, inhibition of COX activity leads to reduced PG production. PGs are important in the onset and maintenance of labour (Keirse 1992). During pregnancy, COX-1 and COX-2 are expressed by the myometrium, decidua, and chorioamnion, with significant up-regulation in the expression of COX-2 prior to the onset of labour at both term and preterm (Slater et al. 1999). This suggests that COX-2 mediates increased PG synthesis in the myometrium at term, highlighting the potential to specifically target and inhibit COX-2. PGs cause an increase in free intracellular calcium levels and amplify the activation of myosin light-chain kinase, which leads to muscle contraction (Molnar & Hertelendy 1990). Therefore, inhibiting PG production can directly reduce myometrial contractility (Van den Veyver & Moise 1993, Doret et al. 2002).
While indomethacin was originally shown to cause a reduction in preterm uterine contractions by up to 7 days (Zuckerman et al. 1974), it was subsequently found to be associated with maternal and fetal side effects when administered in later gestation. Indomethacin freely crosses the placenta and can interfere with PG homeostasis in the fetus, resulting in serious neonatal complications including premature closure of the ductus arteriosus or necrotising enterocolitis (Van den Veyver & Moise 1993, Sood et al. 2011). As a result, indomethacin is usually not administered in pregnancies after 32 weeks’ gestation.
Delaying preterm birth with current therapies: what is the consensus?
Clinicians are limited in the choices of effective preterm therapeutics to use. Cochrane reviews have highlighted that there is not any single tocolytic that can reliably and effectively prevent preterm birth. Rather, these current therapies only postpone the imminent birth by up to 48 h, which is not wholly advantageous for cases of early preterm labour. CCBs have demonstrated benefits over other tocolytics (Flenady et al. 2014b). In comparison to betamimetics, CCBs increased prolongation of pregnancy and importantly resulted in fewer maternal adverse effects and cases of severe neonatal morbidity. CCBs also demonstrated benefits compared to oxytocin receptor antagonists (such as atosiban) and magnesium sulphate in terms of briefly delaying birth, but maternal adverse effects were increased compared with atosiban (Flenady et al. 2014b). This finding was confirmed by another meta-analysis demonstrating that atosiban was associated with fewer maternal side effects than nifedipine (Ali et al. 2019). This study indicated there was no difference in the development of neonatal adverse effects between the two drugs (Ali et al. 2019). Interestingly, NSAIDs and CCBs were similar in their ability to briefly prolong pregnancies (Reinebrant et al. 2015). But, with concerns of use in the third trimester, NSAIDs are limited in their application in late preterm labour. Thus, there is no real consensus that has been reached as due consideration of gestation, location, resource settings, and clinical maternal characteristics impact the ultimate choice of therapy to pursue.
Repurposing drugs as novel therapeutics for the prevention of preterm birth
As discussed above, therapeutic development for preterm birth has been very slow. One approach in obstetric therapeutic development is to repurpose medications. Drug repurposing is the process of discovering new applications for existing drugs (Ashburn & Thor 2004). Traditional pharmaceutical development is expensive and time-consuming; repurposing drugs can fast-track the implementation of an existing intervention for a new indication (Ashburn & Thor 2004) by investigating approved drugs with established safety and pharmacokinetic profiles from extensive testing in clinical trials. This is clearly evident with the history of current tocolytics (as discussed above); CCBs, betamimetics, and indomethacin were all originally developed for cardiovascular conditions or pain. Carefully designed randomised clinical trials will be needed to assess whether some of these repurposed agents may also confer long-term protection to preterm labour or have fewer side effects than current therapies.
There are several important pro-inflammatory factors that are implicated in preterm birth pathophysiology, particularly IL1, IL6, and the TLR4 signalling pathways. There are existing biologics and drugs that target many of these key mediators that are being preclinically investigated for repurposing for treatment of preterm birth. IL1 receptor inhibitors rytvela and anakinra, TLR4 antagonist naloxone, and broad-spectrum chemokine inhibitors (mechanisms of action in Fig. 2) are reviewed in detail elsewhere (Robertson et al. 2020, Coler et al. 2021). For that reason, we have elected to discuss targeting other relevant pro-inflammatory signalling agents that have not been reviewed in detail recently. Further, we will focus on repurposed drug development for preterm birth, using therapies known to be safe during pregnancy that have shown potential as preterm therapies in preclinical studies (overviews in Fig. 2 and 3).
Targeting prostaglandin synthesis and action
As described earlier, NSAIDs, specifically indomethacin, have been used as tocolytics due to their ability to block PG production via inhibition of COX enzymes (Fig. 3). As these drugs act primarily as PG synthesis inhibitors, they are only targeting one aspect of inflammatory signalling that is activated in preterm labour. Additionally, the use of indomethacin has proven to be limited with serious neonatal complications associated with its use, as discussed earlier. However, aspirin, another NSAID, has gained interest as a preterm birth therapeutic.
Aspirin (acetylsalicylic acid) is used in the prevention and treatment of cardiovascular disease. Aspirin is an antiplatelet drug with anti-inflammatory properties, exerting its effects by non-selectively inhibiting COX-1, and to a lesser extent COX-2 enzymes in the cyclo-oxygenase pathway, in turn blocking their enzymatic conversion of arachidonic acid into PGs (Fig. 3) (Atallah et al. 2017). COX-1 is a constitutive enzyme that supports beneficial homeostatic functions, whereas COX-2 is an inducible enzyme, which is up-regulated by inflammatory mediators and increased around the time of labour (Slater et al. 1999).
Interest in aspirin as a potential therapy for preterm birth stemmed from research in preeclampsia prevention; meta-analyses and systematic reviews revealed that trials of prophylactic low-dose aspirin during pregnancy for the prevention of preeclampsia were also associated with reductions in preterm birth (Roberge et al. 2013, Henderson et al. 2014). Use of aspirin in pregnancy is generally considered safe and therefore has been proposed to be a preventative for preterm labour. However, aspirin can cause maternal gastrointestinal bleeding and has recently been shown to be associated with increased postpartum bleeding and postpartum hematoma (Hastie et al. 2021). In terms of fetal effects, aspirin can cross the placenta and reach the fetus, inhibiting fetal platelet aggregation (Leonhardt et al. 2003), and may be associated with neonatal intracranial haemorrhage (Hastie et al. 2021). As the side effects seem to be dose dependent, use of low-dose aspirin is being investigated for preterm birth prevention in randomised control trials (RCTs). Two large RCTs, the ASPIRIN study in nulliparous patients (Hoffman et al. 2020) and the subsequent APRIL study in patients with recurrent preterm birth (Landman et al. 2022), found conflicting results on whether low-dose aspirin has beneficial effects on preterm birth prevention. Specifically, the ASPIRIN trial showed a reduction in the incidence of preterm birth and a decrease in perinatal mortality with aspirin as a preventative, whereas the APRIL trial did not. However, it is important to note that the ASPIRIN trial did not distinguish between spontaneous and indicated (provider-initiated) preterm birth. The APRIL trial was focused on preventing preterm birth in a high-risk population with previous spontaneous preterm birth. Therefore, further investigation in both preclinical and clinical trials would be necessary before recommending aspirin as a preterm birth therapeutic.
Another approach for specific targeting of PGs is via the use of PG receptor antagonists. OBE-022 (ebopiprant) acts by targeting the PGF2a receptor (Fig. 3) and has recently emerged as a once-daily, oral, and selective therapy with promising results (Pohl et al. 2018a). Following success in phase I trials (Pohl et al. 2018b, 2019, Taubel et al. 2018), OBE-022 was advanced to the PROLONG trial, a phase IIa trial in pregnancies with spontaneous preterm labour. Proof-of-concept data were recently presented in an update on the PROLONG trial and demonstrated that OBE-022 was well tolerated and efficacious, particularly when combined with atosiban treatment (ObsEva 2021). The study is anticipated to advance to a phase IIb/III adaptive study. By blocking signalling of specific PG receptors (i.e. PGF2a), this therapy avoids the side effects associated with non-selectively inhibiting the formation of all forms of PGs which are required for fetal development (Pohl et al. 2018a). Thus, this more targeted approach theoretically avoids the serious consequences in the fetus that are associated with NSAIDs, and trial results are awaited with anticipation.
Tumour necrosis factor antagonists
TNF is a key pro-inflammatory cytokine that mediates the inflammatory cascades in both term and preterm labour and has been found to be elevated in amniotic fluid in preterm labour (Lyon et al. 2010). Additionally, TNF plays a role in cervical remodelling and membrane rupture, by promoting the production of MMPs in the cervix and amnion (So et al. 1992, Crider et al. 2005). Administration of TNF has been shown to induce preterm labour in murine and non-human primate models (Silver et al. 1997, Sadowsky et al. 2006). Therefore, TNF poses as an candidate target for intervention in preterm labour.
TNF antagonists (also referred to as anti-TNF drugs) are agents that neutralise TNF (Fig. 2), and each varies slightly in mechanism (Tracey et al. 2008). These drugs can be either fusion proteins (such as etanercept) or neutralising monoclonal antibodies (such as infliximab and adalimumab). They are typically administered for the treatment and management of autoimmune and chronic inflammatory conditions, such as rheumatoid arthritis, and can be continued during pregnancy. There are limited reports on the rate of preterm birth amongst people taking these drugs. In a population-based study, TNF antagonists were shown to be associated with increased risks of preterm birth, caesarean section, and small for gestational age babies (Broms et al. 2020). However, these findings may indicate an association related to the underlying chronic inflammatory disease rather than to the agents. In animal models, TNF antagonists have shown to have beneficial effects in reducing inflammatory markers, preterm birth rates, and fetal injury (Holmgren et al. 2008, Shin et al. 2019). In infection-induced (using lipopolysaccharide (LPS)) models of preterm birth in mice, pre-treatment of mice with TNF antagonists has shown conflicting results: Holmgren and colleagues (2008) showed a decrease in the rate of preterm birth and fetal death, while an earlier study by Fidel and colleagues (1997) did not. More recently, Burdet and colleagues demonstrated that etanercept reduced preterm delivery rates by 30% in rats (Burdet et al. 2013). These differences may be due to the differences between the antibodies or the models. Interestingly, inhibition of TNF did not decrease COX-2 expression which was up-regulated by LPS in the mouse model, indicating that TNF may not directly regulate COX-2 expression in response to LPS (Holmgren et al. 2008). This finding highlights the complexities in attempting to target and inhibit single mediators or pathways involved in preterm labour. However, it should be noted that targeted anti-inflammatory biologics such as TNF or IL1 receptor antagonists have advantages over NSAIDs with their specificity, which reduces off-target effects. Given the involvement of TNF in the inflammatory cascade of preterm birth, there is scope to further investigate the ability of currently available TNF inhibitors to reduce inflammation in human gestational tissues, but without trials in humans, the evidence remains limited.
Proton pump inhibitors
Proton pump inhibitors (PPIs) are conventionally used as treatments for gastroesophageal reflux disease. PPIs act on and inhibit the H+/K+ATPase enzymes, which control the acidification of the stomach. The expression of these enzymes has also been found in the uterus in rats although this has not yet been reported in humans (Crowson & Shull 1992, Jaisser et al. 1993). PPIs are considered safe to use in pregnancy, with studies of large numbers of pregnancies exposed to PPIs prior to conception and throughout pregnancy (>5000 exposures), indicating no increase in birth defects or adverse outcomes (Gill et al. 2009, Pasternak & Hviid 2010).
PPIs are currently under examination as a therapy for preeclampsia. Preclinically, our team demonstrated that PPIs have anti-inflammatory and cytoprotective actions on the dysfunctional placenta and endothelium, with additional vasorelaxant properties on whole vessels (Onda et al. 2017), as well as anti-hypertensive effects in mouse models of preeclampsia (Gu et al. 2022). The effectiveness of PPIs to prevent preeclampsia has been conflicting in clinical trials (Saleh et al. 2017, Cluver et al. 2018, Atwa et al. 2021, Neuman et al. 2022), and further investigation around timing, dosage, and route of administration is required.
Regardless of this fact, the PPIs have demonstrated properties that suggest they may be candidate preterm birth therapeutics. Emerging investigation in preclinical studies for this application is underway. An early study has shown that omeprazole can reduce spontaneous and calcium-induced myometrial contractions in in vitro models testing myometrium collected from pregnancy (Yildirim et al. 2001). More recently, a variety of PPIs were examined in human myometrial tissue bath experiments. Pantoprazole demonstrated the most effective relaxant action, greater than nifedipine and other tocolytics used as comparators (Terranova et al. 2014).
Lansoprazole was also uncovered as a strong potential therapeutic candidate for preterm birth via computational identification methods using transcriptomic data (Le et al. 2020). The authors further validated this finding with a pilot study of a mouse model of LPS-induced preterm birth, which showed reduction in fetal loss with lansoprazole treatment.
PPIs are hypothesised to have effects on the myometrium through pathways other than directly influencing the H+/K+ATPase. Whilst the specific mechanisms are not clear, it is thought that pantoprazole may interfere with the regulation of intracellular calcium concentrations (Fig. 3) (Terranova et al. 2014). In animal models, omeprazole reduced smooth muscle tone of the trachea (Rhoden et al. 1996) and lower oesophageal sphincter (Welsh et al. 2014). These papers suggest PPIs may exert muscle relaxant effects via inhibiting the Rho/Rho-associated protein kinase (ROCK) pathways (Fig. 3). The Rho/ROCK pathway in myometrial cells is known to be involved in uterine contractility, and inhibition of this pathway promotes muscle relaxation (Lartey & Lopez Bernal 2009). The ability of PPIs to potently reduce myometrial contractions and the safety profile of these drugs support the further investigation into repurposing PPIs as promising candidates for preterm labour suppression.
Statins
Statins are a class of drugs that potently inhibit cholesterol production and are used as a preventative/treatment for cardiovascular disease. They inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway. However, statins have also received interest as candidate drugs for the treatment and prevention of preeclampsia. Importantly, statins have anti-inflammatory and cytoprotective properties and can inhibit vascular smooth muscle contractions (Perez-Guerrero et al. 2005). Pravastatin has been shown preclinically to have beneficial effects on placental and systemic vascular disease by up-regulating antioxidant pathways, reducing the production of anti-angiogenic factors and improving endothelial migration and adhesion (Brownfoot et al. 2016, de Alwis et al. 2020). For these reasons, pravastatin has been assessed in several clinical trials (Costantine et al. 2016, 2021, Ahmed et al. 2020).
Furthermore, these anti-inflammatory properties make the statins desirable candidates for the prevention and/or treatment of preterm birth and are now being examined in preclinical studies. Direct anti-inflammatory effects of pravastatin and simvastatin on pregnant mouse cervix and uterus were examined in an LPS-induced mouse model of preterm birth. Pre-treatment with either of these statins was associated with a decrease in the expression and production of pro-inflammatory cytokines in the cervix and uterus of mice (Basraon et al. 2012). Interestingly, simvastatin emerged as the stronger anti-inflammatory compared with pravastatin as it reduced a greater number of cytokines. The anti-inflammatory effects of simvastatin have been reiterated in another preclinical study (Boyle et al. 2019).
Further to anti-inflammatory actions, statins were demonstrated to prevent cervical remodelling and inhibit myometrial contractions in mouse and human tissues and prevent preterm birth in a mouse model (Gonzalez et al. 2014, Boyle et al. 2019). Gonzalez and colleagues (2014) proposed that statins may be exerting these actions by activation of the heme oxygenase/carbon monoxide (HO-1/CO) pathway. HO-1 has previously been reported to diminish myometrial contractility by increasing the production of CO in myometrial cells, which in turn acts as a messenger to activate soluble guanylate cyclase activity, thus increasing the production of cyclic GMP (Fig. 3) (Acevedo & Ahmed 1998). This leads to smooth muscle relaxation. Additionally, Boyle and colleagues (2019) demonstrated that simvastatin could inhibit the Rho/ROCK pathway which, as described earlier, is a pathway associated with muscle contraction (Fig. 3). In terms of preventing cervical remodelling, pravastatin achieved this by (i) decreasing MMP activity and (ii) inhibiting complement activation (Fig. 2) (Gonzalez et al. 2014). The regulation of complement activation by the statins in animal models of other pregnancy complications such as preeclampsia has been previously reported, thus highlighting that this may be a pathway worth targeting (Kumasawa et al. 2011, Singh et al. 2011).
Collectively, these preclinical findings have convincingly presented the statins as promising candidates. As such, pravastatin has been recently taken into the clinical trial phase. The PIPIN trial in the UK is investigating the feasibility of pravastatin as a treatment for preterm birth (Whitaker et al. 2019). So far, no adverse effects have been reported in the participants who received pravastatin.
Currently, statins are classified as Category X for use in pregnancy by the US FDA, meaning that ‘studies in animals or humans have demonstrated fetal abnormalities and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits’, and the UK NICE guidelines advise to avoid their use in pregnancy. While not approved for therapeutic use in pregnancy yet, there is now substantial evidence (Zarek & Koren 2014) to refute the original study (Edison & Muenke 2004) that claimed that statins were teratogenic.
Further to this, as pravastatin is a hydrophilic drug, it should not pass easily through the placenta to the fetus (Hamelin & Turgeon 1998). This is supported with evidence that pravastatin is not detectable (Costantine et al. 2016), or at very low concentrations, in the umbilical cord at birth (Ahmed et al. 2020, Costantine et al. 2021). Moreover, clinical trials assessing pravastatin have not shown any adverse fetal effects (Costantine et al. 2021). Therefore, there is momentum with supporting evidence to indicate that the statins are safe in pregnancy or that any risks may outweigh the benefits of the treatment for preeclampsia or preterm birth.
Enhanced activity and efficacy – combination therapeutic approaches
Another approach to enhance therapeutics may be combination therapy approaches, whereby drugs with complementary actions that act via different mechanisms can be dually administered (Vogel et al. 2014). These drugs could have additive or synergistic effects. It is postulated that combination therapy can enhance the overall effectiveness of the treatment, reducing dosage and frequency, thus averting adverse effects (Vogel et al. 2014). The current tocolytic approach to suppress uterine contractions is unlikely to achieve more than delaying birth for a few days, unless the underlying inflammatory drivers, which can also cause fetal inflammatory injury, are additionally dampened. Therefore, when considering combination therapies, both inflammation and myometrial contractions should both be targeted. The combination of a CCB (to directly inhibit uterine contractions) and indomethacin (to reduce inflammation) is an example of this approach. A recent RCT found that combination therapy of nifedipine and the anti-inflammatory NSAID indomethacin between 26 and 34 weeks’ gestation was a more effective tocolytic therapy than monotherapy of either drug (Kashanian et al. 2020). Combination therapy of nifedipine and indomethacin increased the proportion of pregnancies where contractions were inhibited for 48 h and for 7 days. Additionally, gestational age at birth and neonatal weight were significantly increased by combination treatment compared with either drug alone. There is currently a single-hospital RCT being conducted with Sudanese participants diagnosed with threatened preterm labour between 25 and 34 weeks investigating the nifedipine/indomethacin combination compared with nifedipine monotherapy (Ibrahim et al. 2021). Optimistically, further well-designed trials will reveal any clear advantages for combination therapy. Synergistic effects between therapies should also be investigated in preclinical models of preterm labour, to determine how the targeted pathways may interact and whether adverse impacts on the fetus may result. Importantly in cases of infection, or suspicion of infection, antibiotics will also need to be administered, and therefore any contraindications need to be considered to ensure drug activity is not disrupted.
Targeted drug delivery to enhance therapeutic action on myometrial contractions
While many of these repurposed therapies demonstrate promise, potential off-target effects are still of concern when administering any drug in pregnancy, as they may inadvertently harm the developing fetus, as was seen in the Dutch STRIDER trial with sildenafil citrate (Groom et al. 2018). However, targeted delivery systems such as the use of advanced targeted nanoparticles may prevent these off-target effects by allowing delivery of therapeutics to specific cells, organs, or tissues (Pritchard et al. 2021). Targeted myometrial drug delivery using nanoparticles has recently been reviewed in thorough detail (Coler et al. 2021, Pritchard et al. 2021) and will be briefly reviewed here. Tocolytics can be delivered in nanocarrier systems such as nanoliposomes. Refuerzo and colleagues (2015) first examined the selectivity and efficacy of indomethacin packaged in liposomes. Encapsulated indomethacin resulted in a 7.6-fold reduction in the amount of drug that transferred to the fetus compared with systemic administration. However, the encapsulated drug did not differ in efficacy compared with the non-packaged drug (Refuerzo et al. 2015). To improve specificity, targeted liposomes were developed. The oxytocin receptor is highly expressed by myometrial cells during pregnancy and is specific to the uterus and breast tissue (Fuchs et al. 1984), thus providing a means of targeting therapeutics to the myometrium. In a subsequent study, the addition of an oxytocin receptor antagonist to the liposomal surface increased selective targeting to the uterus and resulted in a 15% reduction in preterm birth in a mouse model (Refuerzo et al. 2016). The benefit of targeting to the oxytocin receptor to deliver known tocolytics, including nifedipine, salbutamol, and indomethacin, has also been shown (Paul et al. 2017). This study elegantly demonstrated the specificity of the liposomes in binding to the oxytocin receptor in mouse models of preterm birth. In pregnant mice, transplacental passage of the liposomes to the fetus was not observed, but there was some localisation to the mammary tissue (Paul et al. 2017). So far, nanoparticle-based targeted delivery systems for preterm birth have not reached clinical trials; however, the preclinical data are very promising and the flexibility to deliver different classes of drugs makes this delivery system an exciting innovation.
Future perspectives
Repurposing existing drugs brings significant advantages to the therapeutic development pipeline. The known safety profiles, established mechanisms, and previous extensive testing make it quicker, cheaper, and easier to implement these therapies in trials. However, it must be considered that this approach is limited to existing and available drugs. The cost of therapies must also be considered in therapeutic development, as low- and middle-income populations are where preterm birth rates are highest.
A multifaceted approach is essential for therapeutic development, where human in vitro work, animal models, computational analysis, and evidence from epidemiological studies can inform each other and guide which drugs to investigate further in clinical trials. In addition, clinical trials must be carefully designed to maximise their impact. Meta-analyses of preterm birth tocolytics continually call for better designed trials and standardised reporting of outcomes, and this must be adopted by the field.
Innovation in therapeutic development for preterm birth will involve a combination of repurposing therapies (e.g. proton pump inhibitors (PPIs), statins, and aspirin), targeted delivery approaches (e.g. nanoliposome encapsulation), and inhibition of specific key pathways (e.g. TNF inhibitors and PG receptor antagonists). The potential that some of these drugs have shown in clinical trials for the prevention of preeclampsia is exciting for the area of preterm birth therapies. We propose that efforts should be focused on therapies that target both the underlying inflammation and downstream myometrial contractions.
Conclusion
The rates of preterm birth remain high, and despite research focused towards understanding the pathophysiology of preterm birth and development of new therapeutics, there has not been a substantial reduction in this rate. Current tocolytics are highly limited in their effectiveness and only provide a short delay in delivery. As preterm birth is a syndrome of heterogeneous aetiologies, therapeutic development is challenging. Further research aimed at elucidating the mechanisms of preterm birth pathophysiology is essential for the generation of predictive, screening, and therapeutic tools. Repurposing therapies poses as an exciting approach for the path forward in innovative therapeutic development for preterm birth. Importantly, preterm birth prevention encapsulates more than medical intervention with tocolysis. Preventative public health measures are also crucial to tackling the underlying causes and risk factors of preterm birth.
Declaration of interest
The authors declare that there are no conflicts of interest. Natalie Hannan is on the editorial board of Reproduction. Natalie was not involved in the review or editorial process for this paper, on which she is listed as an author.
Funding
This study was supported by an ARC Future Fellowship to NJH (FT210100193) and a University of Melbourne postgraduate research scholarship (Felix Meyer Scholarship in Obstetrics & Gynaecology) to BMA.
Author contribution statement
BMA and NJH planned the scope, wrote and edited the manuscript, planned/prepared figures, and contributed guidance to other contributing authors. NKB and NDA contributed to writing and editing of the manuscript. TKL contributed to final edits and version of the manuscript. All authors have read and agreed to publish the present version of the manuscript.
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