Across the 153 candidates identified for prevention and/or treatment of pre-eclampsia, only one (0.7{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) was approved and on the market for the treatment of pre-eclampsia/eclampsia (magnesium sulphate). An additional 13/153 (8.5{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) candidates were approved for other clinical conditions and used off-label for pre-eclampsia.
Of the 153 candidates, 90 (58.8{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were currently actively investigated and 63 (41.2{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were not (i.e. no published activity in the last 3 years; Fig. 1A). In total, 66 candidates were in the preclinical stage (43.1{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}), 11 candidates were in phase I (7.2{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}), 32 candidates were in phase II (20.9{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}), 43 candidates were in phase III (28.1{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) and 1 candidate was in phase IV (0.7{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}; Fig. 1B). Thirty-eight candidates were classified as dietary (24.8{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}), 25 were biological (16.3{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) and 90 were classified as drugs (58.8{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}; Fig. 1C). A quarter of all candidates (38 candidates, 24.8{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were new chemical/biological entities, while the remaining were repurposed (115 candidates, 75.2{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}; Fig. 1D).
Details of the candidates in the R&D pipeline for pre-eclampsia. Summary of the 153 candidates in the R&D pipeline for the prevention and treatment of pre-eclampsia from 2000 to 2021. The proportion of candidates A in active development, and inactive (no publications since 2018), B in each phase of the development pipeline C classified as drugs, dietary supplements or biologicals and D classified as new chemical or biological entities or repurposed drugs
Of the 87 candidates in phases I to IV, 55 were excluded from further analysis (Fig. 2, Additional file 2: table S5), leaving 32 candidates. Of these, seven were ranked as high potential, eight ranked as medium potential and 21 ranked as low potential. Some candidates were being investigated as both a treatment and a prevention agent, so the total number of candidates ranked for potential is greater than the total number of unique candidates.
Flowchart of assessment of candidates against the eligibility criteria
Prevention of pre-eclampsia
There were ten candidates under investigation for pre-eclampsia prevention in phase III (probiotic lactobacilli, vitamin D, omega-3 fatty acids, l-arginine, coenzyme Q10, dalteparin, esomeprazole, pravastatin, selenium and vitamin B12; Fig. 3A); five in phase II (chloroquine/hydroxychloroquine, l-citrulline, dydrogesterone, metformin, ozagrel, Fig. 3B) and two in phase I (pentaerythrityl tetranitrate and salsalate; Fig. 3C). Five candidates were ranked as high potential and four as medium potential. Results for low-priority candidates are included in supplementary data (Additional file 3).
Visual representation of target product profile matching for candidates to prevent pre-eclampsia. A traffic light system to visualise each candidate for pre-eclampsia prevention at A phase III, B phase II and C phase I clinical development. Candidates are classified as met preferred (dark green), met minimum (light green), partially met minimum (yellow) and did not meet the minimum (red) requirements in the target product profiles. When insufficient information is available for a specific variable, they have been classified as not yet known (grey). *Target country is classified as trials being conducted in HIC and LMIC (dark green), HIC only or LMIC only (both yellow) or country not stated (grey). **Stability has been classified as does not require cold chain (green), requires cold chain (red) or unsure (grey). #WHO EML is classified as the candidate is already on the WHO EML list (green) or the candidate is not on the WHO EML list (red). The final rank has been determined by quantification of the matching to the target product profiles (see Additional file 1: tables S3 and S4 for details of quantification coding), with efficacy and safety given a greater weight than other variables. HIC high-income country, LMIC low- or middle-income country, EML essential medicines list
Phase III candidates
Using the TPP ranking, l-arginine, esomeprazole, and vitamin D were ranked as high potential for preventing pre-eclampsia. l-Arginine, an essential amino acid, met the TPP preferred requirements for six variables, including clinical efficacy (Fig. 3A). A meta-analysis of seven l-arginine supplementation trials (884 women) conducted across high- and low-middle-income countries suggest that l-arginine may protect against pre-eclampsia and subsequent preterm birth, although the authors highlighted that further large, high-quality trials were needed [22]. Safety was only partially met, as one trial indicated a concern that women with diabetes should not consume the l-arginine supplement, which came in two nutritional bars per day [23]. However, this may be unnecessarily cautious considering there are no serious safety concerns with l-arginine in pregnancy [22, 23]. Esomeprazole, a small proton-pump inhibitor, met the TPP preferred or minimum requirements for seven variables; however, clinical efficacy remains uncertain (Fig. 3A). As of May 2021, there are 12 ongoing or completed esomeprazole trials for pre-eclampsia, three of which are investigating esomeprazole for pre-eclampsia prevention. Two trials are being conducted in Australia [24, 25] and one in Egypt [26]. Vitamin D met the preferred or minimum requirements for eight variables, including the minimum for clinical efficacy. A 2020 meta-analysis indicated that vitamin D supplementation reduced pre-eclampsia (4 trials, 499 women, RR 0.48, 95{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} CI 0.30–0.79; moderate-certainty evidence) [27]; however, one included trial has since been retracted [28]. In addition, a 2022 systematic review of 22 observational studies showed that women with insufficient or deficient vitamin D levels during pregnancy had higher odds of pre-eclampsia than vitamin D-replete women [29].
Three dietary supplements (omega-3 fatty acids, selenium and probiotic lactobacilli) and the low molecular weight heparin (LMWH) dalteparin were ranked as medium potential and all met the TPP requirements for most variables (Fig. 3A). Questions remain about the clinical efficacy of omega-3 fatty acids — while a 2020 meta-analysis (20 trials, 10,806 women) found that omega-3 fatty acid supplementation may reduce the risk of pre-eclampsia in women with low-risk pregnancies (RR 0.84, 95{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} CI 0.69–1.01) [30], a 2019 trial by Makrides et al. (which was not included in the 2020 meta-analysis) of 5517 women showed that daily fish oil capsules containing 900mg n-3 long-chain polyunsaturated fatty acids had no effect on pre-eclampsia [31]. A 2015 UK trial found that selenium supplementation in 230 pregnant women with a selenium deficit reduced the odds of pre-eclampsia (OR 0.3, 95{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} CI 0.09–1.00) [32]; similar results were observed in a smaller Iranian trial of 166 pregnant women supplemented with selenium [33]. Although there is currently a lack of evidence on the clinical efficacy of probiotic lactobacilli in preventing pre-eclampsia, registered phase III trials in Sweden and the USA will further elucidate its potential and hence its ranking may change [34, 35]. Meta-analysis of LMWH trials, including three trials specifically using dalteparin, found a reduced risk of pre-eclampsia with all LMWH (797 women, RR 0.37, 95{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} CI 0.22–0.61) and specifically for dalteparin (190 women, RR 0.27, 95{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} CI 0.11–0.63), compared to no treatment [36]. The dalteparin trials required a normal thrombophilia screen (a combination of tests to identify deficiencies in a number of natural anti-coagulants) prior to inclusion. Should this companion diagnostic be required for real-world use, it may hinder the widespread implementation [37].
Phase II candidates
The antimalarial drug chloroquine/hydroxychloroquine and the oral antihyperglycemic agent metformin were ranked high potential, with both meeting the preferred or minimum requirements for most TPP variables. However, clinical efficacy remains unknown. A 2021 meta-analysis of seven observational studies found that hydroxychloroquine reduced the odds of pre-eclampsia in pregnant women with systemic lupus erythematosus, compared to no hydroxychloroquine (680 women, OR 0.35, 95{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} CI 0.21–0.59) [38]. A trial of this treatment in 50 pregnant women without systemic lupus erythematosus has also been registered [39]. A 2017 systematic review of metformin in pregnancy found five trials and four cohort studies: while there was no difference in the risk of pre-eclampsia compared to placebo, when compared to insulin, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia [40]. A trial of metformin in 414 pregnant women with a high risk of pre-eclampsia in Qatar has been registered [41].
Phase I candidates
No candidates ranked high or medium potential.
Treatment of pre-eclampsia
Four candidates have been investigated for the treatment of pre-eclampsia through phase III trials (sulforaphane, esomeprazole, pravastatin and resveratrol; Fig. 4A), nine candidates in phase II (Curcuma longa, vitamin B3, serelaxin, sildenafil citrate, tadalafil, rosuvastatin, iloprost, ozagrel and metformin, Fig. 4B) and six in phase I (vardenafil, Purnica granatum extract, sulfasalazine, conestat alfa, S-nitrosoglutathione and RMC 035; Fig. 4C). Two candidates were ranked as high potential and four as medium potential. Results for low-priority candidates are included in supplementary data (Additional file 3).
Visual representation of target product profile matching for candidates to treat pre-eclampsia. A traffic light system to visualise each candidate for pre-eclampsia treatment at A phase III, B phase II and C phase I clinical development. Candidates are classified as met preferred (dark green), met minimum (light green), partially met minimum (yellow) and did not meet the minimum (red) requirements in the target product profiles. When insufficient information is available for a specific variable, they have been classified as not yet known (grey). *Target country is classified as trials being conducted in HIC and LMIC (dark green), HIC only or LMIC only (both yellow) or country not stated (grey). **Stability has been classified as does not require cold chain (green), requires cold chain (red) or unsure (grey). #WHO is classified as candidate is already on the WHO EML list (green), or candidate is not on the WHO EML list (red). The final rank has been determined by quantification of the matching to the target product profiles (see Additional file 1: tables S3 and S4 for details of quantification coding), with efficacy and safety given a greater weight than other variables. HIC high-income country, LMIC low- or middle-income country, EML essential medicines list
Phase III candidates
Sulforaphane (broccoli extract) met the requirements for four TPP variables and was ranked as medium potential. Currently, the clinical efficacy, safety and adherence rates remain unknown, with a trial recruiting 180 women currently underway in Australia [42]. Pravastatin was also ranked medium as it met six of the TPP requirements, though a 2020 trial including 62 women with early-onset pre-eclampsia reported no effect of pravastatin on maternal plasma soluble fms-like tyrosine kinase-1 (sFlt-1) levels or pregnancy duration [43]. Difficulties in recruiting women may mean the study was underpowered.
Phase II candidates
Metformin ranked as high potential for the treatment of pre-eclampsia, having met the preferred or minimum requirements for six TPP variables. Clinical efficacy remains unknown, but a 2021 trial of 180 women with preterm pre-eclampsia in South Africa found that metformin significantly prolonged pregnancy by a mean of 7.6 days compared to placebo [44]. Rosuvastatin ranked as medium potential, as it met the preferred requirements for four of the variables. Clinical efficacy remains unknown and two trials are registered in Israel and Egypt [45, 46]. Vitamin B3 also ranked medium potential and met the requirements for five variables; however, clinical efficacy remains unknown, with a phase II trial in the USA registered in 2018 [47].
Phase I candidates
Sulfasalazine, a drug used for inflammatory bowel disease, was ranked as high potential as it met the preferred or minimum requirements for six TPP variables. The outcomes of an Australian phase I clinical trial investigating sulfasalazine as a treatment for pre-eclampsia will provide important data on clinical efficacy [48].
Preclinical candidates
Of the 66 candidates in preclinical development, 26 were excluded due to potential adverse effects in humans, or the target of the candidate being unclear. From the remaining 40 candidates, 32 candidates (80{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were active and 8 (20{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were inactive (Fig. 5A). A total of 18 (45{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were drugs, 11 (27.5{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were biologics and 11 (27.5{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) were dietary supplements (Fig. 5B). Repurposed medicines accounted for 50{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} of the preclinical candidates (20 candidates; Fig. 5C). Eleven candidates have been proposed for the prevention of pre-eclampsia (Table 2), 24 as a treatment of pre-eclampsia (Table 3) and 5 for both prevention and treatment (Tables 2 and 3).
Details of the included preclinical candidates in the research and development pipeline for pre-eclampsia prevention and treatment. Summary of the preclinical candidates in the R&D pipeline for the prevention and treatment of pre-eclampsia from 2000 to 2021. The proportion of candidates A in active development, and inactive (no publications since 2018); B classified as drugs, dietary supplements or biologicals; and C classified as new chemical or biological entities or repurposed drugs
The most common drug subclass was amino acid/peptides (7 candidates; 17.5{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}) and polyphenols (7 candidates; 17.5{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}), followed by small interfering RNA (siRNA), messenger RNA (mRNA) or DNA-based medicines (5 candidates; 12.5{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac}). Other medicine subclasses included antioxidants, small molecules, cell therapies, hydrogen sulphide donors, statins, herbal medicines, vascular agents and macronutrients. We identified some concerns with the preclinical efficacy evidence for half of the preclinical candidates (20 candidates). These concerns included the use of extremely high doses of the candidate in preclinical studies (8 candidates). Other concerns included results that did not show any positive effects, the use of inappropriate animal models of pre-eclampsia and the use of inappropriate controls or statistics.