The quality of medicines for the prevention and management of hypertensive disorders of pregnancy: A systematic review

The quality of medicines for the prevention and management of hypertensive disorders of pregnancy globally is a critical challenge in the reduction of maternal mortality rate. We aimed to conduct a systematic review of available studies on the quality of the eight medicines recommended globally for the prevention and management of hypertensive disorders of pregnancy. We searched five electronic databases- Ovid MEDLINE, EMBASE, CINAHL, ProQuest and Cochrane Library, and also grey literature, without year or language limitations. Any study assessing the quality parameters (Active Pharmaceutical Ingredients, pH, sterility, solubility, impurities) of medicines by using any valid laboratory methods was eligible. Two reviewers independently screened the studies, extracted data and applied Medicine Quality Assessment Reporting Guidelines tool for quality assessment. Results were narratively reported and stratified by the drug types. Of 5669 citations screened, 33 studies from 27 countries were included. Five studies reported on the quality of magnesium sulphate—two (Nigeria and USA) found substandard medicine due to failing API specification and contaminants, respectively. Another study from Nigeria and a multi-country study (10 lower-middle- and low-income countries) found poor-quality due to failing the pH criteria. Seven of eight studies evaluating aspirin found quality issues, including degraded medicines in five studies (Brazil, USA, Yugoslavia and Pakistan). Five studies of calcium supplements found quality issues, particularly heavy metal contamination. Of 15 antihypertensives quality studies, 12 found substandard medicines and one study identified counterfeit medicines. This systematic review identified pervasive issues of poor-quality medicines across all recommended medicines used to prevent or treat hypertensive disorders of pregnancy, raising concerns regarding their safety and effectiveness.


Introduction
Globally, an estimated 287,000 women die each year due to complications during or following pregnancy and childbirth, resulting in a global maternal mortality ratio (MMR) of 223 maternal deaths per 100,000 live births [1].Of these, 95% occurred in low-and middle-income countries (LMICs), with the highest MMRs in Sub-Saharan African and South Asian countries [1].Hypertensive disorders of pregnancy (HDP), the second leading direct cause of maternal mortality, are estimated to account for 27,830 maternal deaths each year [2].They are a heterogenous group of disorders, including chronic hypertension, gestational hypertension, preeclampsia/eclampsia and preeclampsia superimposed on chronic hypertension [3].
Management of HDP involves the use of medicines repurposed from other hypertensive conditions, which remain off-label for use in pregnant women [4].The World Health Organization (WHO) and National Institute for Health and Care Excellence (NICE) guidelines recommend that women at increased risk of preeclampsia receive low-dose aspirin from 12 weeks of gestation, onwards [5,6].They also recommend calcium supplementation (1.5-2 gram/day orally) to women living in regions with low dietary calcium intake [6,7].Antihypertensive medicines, such as labetalol, nifedipine, methyldopa, hydralazine, amlodipine and enalapril, are recommended for hypertension management depending on the severity [5,6,8].Magnesium sulphate is recommended for the prevention and management of eclamptic seizures [5,6].
Access to good-quality medicines is critical for the management of HDP [9].According to WHO, 10.5% of all available medicines for any condition are substandard or falsified globally, and this is more prevalent in low-and middle-income countries (LMICs) [10].Substandard medicines are manufactured by registered pharmaceutical companies, but fail to meet quality specifications [11,12].Falsified medicines are those that are manufactured and packaged to purposively deceive consumers, and may contain poor quality ingredients or no active ingredients at all [11,12].Previous systematic reviews have identified evidence of poor-quality in medicines used for pregnancy complications, including postpartum haemorrhage and preterm birth [13,14].Ineffective medicines thus present a major challenge to reaching the Sustainable Development Goals of ending preventable maternal and newborn mortality [12].
Several studies have been published on the quality of medicines used for HDP, however their findings have not been evaluated systematically.One previous systematic review reported on some maternal medicines including magnesium sulphate [15] without considering other medicines for HDP.Therefore, this review aimed to identify, critically appraise and synthesize the findings of studies on the quality of commercially available medicines recommended for prevention and treatment of HDP.

Methods
This review followed the standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews.The protocol was preregistered on PROSPERO (CRD42023425055).
We pre-specified nine medicines (Table 1) on the basis of current WHO and NICE guidelines on the prevention and management of HDP.Detail of inclusion and exclusion criteria are mentioned in the appendix (see S2 Text).Outcome of interest for this review included multiple parameters used to assess medicine quality, including any one or more of macroscopic appearance, extractable volume, pH range, active pharmaceutical ingredient (API) content, sterility, solubility, impurities or related substances, as well as packaging, labelling, storage and transportation conditions.We reported failure rates on the quality of studied medicines according to the parameters assessed by the authors against the pharmacopoeia specification (whether it was International Pharmacopoeia, US Pharmacopoeia, British Pharmacopoeia or other relevant Pharmacopoeia) or the manufacturer standard of each included study.Medicines were considered to be substandard if they did not comply with these standards on specified API content, impurities, or containing related substances.Medicines were considered to be falsified (or counterfeit) if they had no active ingredients, and were considered falsified by the authors of the study in question.

Electronic databases and searching methods
A comprehensive search of five electronic databases-Ovid MEDLINE, EMBASE, CINAHL, ProQuest and Cochrane Library-was conducted on 28 th October 2022.The search strategy was created with the help of an experienced librarian (see S1 Text).The search was complemented by reviewing the reference lists of all included articles.Grey literature searches included unpublished studies identified through contacts with investigators who had conducted the studies.All recovered citations were uploaded into EndNote, and then screened using Covidence.Title and abstract screening, and subsequent full-text review was conducted by two independent reviewers, with conflicts resolved via discussion or consulting a third reviewer.Reports in languages other than English were first screened with an online translation tool (Google Translate) and subsequently translated by a native speaker to confirm eligibility and for data extraction and quality assessment.

Data extraction and quality assessment
Data for this review were extracted from included studies using Covidence.Variables of interest were country, sample collection year, types of outlets where samples were collected, country of manufacture, types of tests performed, total number of samples assayed, which pharmacopoeia or standard method was used and data relevant to outcomes of interest.
We assessed the quality of all included studies using the Medicine Quality Assessment Reporting Guidelines (MEDQUARG) checklist for reports of surveys of the quality of medicine [16].Each study was graded on following domains: (1) survey details, (2) definition of substandard, falsified and degraded medicines, (3) types of outlets sampled, (4) sampling design and sample calculation, (5) type and dosage of units collected per outlet, (6) random sampling, (7) samplers' detail, (8) packaging assessment, (9) statistical methods, (10) chemical analysis description, (11) method validation details and (12) blinding or chemical assessors.There is no established threshold using the MEDQUARG tool to define study quality, hence the studies were categorised using the approach of Torloni et al., which similarly evaluated studies on the quality of maternal medicines [13], where good methodological quality was defined as those with MEDQUARG score � 6, and a score < 6 as low methodological quality.Two reviewers performed data extraction and quality assessment independently, with conflicts resolved via discussion or consultation with a third reviewer.

Data synthesis and statistical analyses
Data were presented descriptively.We reported on the prevalence of failed samples due to API content (whether too low or too high), sterility, pH and presence of impurities or related substances.Included studies and extracted data were organised by medicine type.We also reported the country where the study was conducted, and categorised that country income level, using the World Bank 2022 classification, and by type of outlets where the samples were collected.
Studies were conducted between 1979-2021 and in a wide range of countries: three studies in low-income countries (LICs), 14 in upper-middle income countries (UMICs) and eight in high-income countries (HICs).Nineteen studies reported the setting from where medicines were sampled.This included patent medicine stores, wholesale and retail pharmacy stores, midwifery clinics, primary health care centres, state hospital, pharmacy depot, warehouses, compounding pharmacies, central medical stores, NGO central stores, basic pharmacies, pharmaceutical companies, registered and unregistered pharmacies, informal drug stores, and pharmacy chain stores.In total, 23 (69.7%) studies were of good methodological quality (score � 6).

Magnesium sulphate
Five studies assessed the quality of magnesium sulphate (  [17].Two studies from Nigeria-163 samples in the 2018 study and 90 samples in the 2021 study-reported that all samples passed sterility testing [19,21].In the 2018 study, four of 163 samples did not meet API content specification and were reported as substandard [19]. In contrast, the 2021 Nigerian study [21] and post-marketing surveillance study from Ethiopia (13 samples) [18] reported all samples passed API content assays.The UNCoLSC study assessed a total 19 samples from 10 different countries in which two samples (one from Burkina Faso and one from Vietnam) failed to meet pH specifications [50].Similarly, the Nigerian study (2021) reported 40 of 90 samples as poor-quality due to not meeting pH criteria [21].
Whereas the Nigerian (2018) and Ethiopian (2015) studies reported all samples passed the criteria for pH testing [18,19].

Calcium supplements
Five studies assessed the quality of calcium supplements (see Table 4).All five studies tested for the presence of heavy metal impurities, such as lead or mercury [30][31][32][33][34]. Three studies from the USA (22 samples), Brazil (23 samples) and Pakistan (27 samples) identified lead contamination in 36.4%,60.9% and 88.9% of samples respectively [32][33][34].The other two studies, both from the USA in 1988 (ten samples) and 2005 (three samples), detected mercury and other trace elements in only a single sample in each study [30,31].The Brazilian study also assessed API content and reported 31.1% (seven out of 23 samples) of calcium supplements were substandard with an API content below the specification range by Brazilian Pharmacopoeia [32].

Antihypertensive medicines
We found 15 studies on the quality of antihypertensives (Table 5) [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49].Seven studies evaluated the quality of amlodipine-two studies from India and Nepal found no evidence of poorquality amlodipine [36,38].In contrast, a Nigerian study reported three of ten (30.0%) amlodipine samples were counterfeit as they were unregistered within regulatory bodies, and their API content did not comply with British Pharmacopoeia standard.[37] A study in Cambodia found seven amlodipine samples (8.9%) did not meet the API content and uniformity criteria according to the US Pharmacopoeia and British Pharmacopoeia [40].Another two studiesone conducted in 10 different African countries [35] and the other in Nigeria [41]-reported 87 (28.5%) and 48 (24.6%) amlodipine samples as substandard, respectively, due to failure to meet API specification.An additional Nigerian study reported four (50.0%) samples as substandard: one sample (12.5%) did not meet the API specification and three (37.5%)samples failed in friability and hardness criteria [39].Two studies assessed nifedipine quality-one from Germany reported 60.3% samples of nifedipine did not comply with the German Federal Health Authority and US Pharmacopoeia API specification, and 27.9% of packaged and 76.5% of unpackaged nifedipine did not pass the light stability test [43].Whereas, the other study from Nigeria concluded that 78 nifedipine samples (76.5%) were of poor quality, with 31 (30.4%)samples failing to comply with API specifications of US Pharmacopoeia and International Pharmacopoeia, and 76 (74.5%) samples showing nitrophenylpyridine impurities above the acceptance range [42].
Three studies from Nigeria [45], Rwanda [44] and Brazil [46], assessed methyldopa quality.A Nigerian study and Brazilian study reported one (25.0%)sample and ten (50.0%) samples as substandard, due to not meeting the API specification [45,46].The study from Brazil also reported that ten (50.0%) samples failed to meet the criteria of API content.In contrast, the Rwandan study reported all three samples cleared the physicochemical parameters tested immediately after their purchase [44].
Three studies assessed enalapril quality-two from Brazil [46,47] and one from Turkey [48].One of the Brazilian studies (2011; 20 samples) reported 100% of samples were substandard due to failure to meet Brazilian Pharmacopoeia API specification [46].The study from Turkey reported that all eight samples met the criteria of API content and friability, however, all samples failed in the hardness test [48].The other Brazilian study (2014) detected contaminants (including aluminium, gold, bromine, cerium, cobalt, hafnium, lanthanum, antimony, scandium, samarium, thorium, zinc, chromium) in all five samples [47].Only one study on the quality of hydralazine was identified, conducted in the USA in which 12 (75.0%)samples were found to be poor-quality due to presence of impurities resulting from degradation i.e. hydrazine, above the acceptance limit [49].for many obstetric medicines has not been established [53,54].Contaminants-such as those reported for calcium, enalapril and magnesium sulphate [17,[30][31][32][33][34]47]-are worrisome.In the absence of comprehensive toxicology evaluations, we can only speculate that these substances might jeopardise women's and newborn's health [55].
Poor-quality medicines can also reduce health workers' confidence in the effectiveness of treatments, and otherwise impair public trust in the health system [11,14].In addition, it affects public health due to poor health outcomes and also have adverse impacts due to additional health systems costs, wastage of resources, and increased out-of-pocket costs [11].For instance, a study by Ozawa et al (2018) estimated the economic burden of substandard and falsified antimalarial and antibiotics in LMICs to range from $10 billion to $200 billion [10].Currently, there are no cost-effectiveness studies on impact of poor-quality maternal medicines specifically, however, a study has shown the significant costs of caring for women with preeclampsia [56], which would be incurred if not effectively prevented or managed.
While this review was limited to medicines for HDP, quality issues affecting other medicines used in pregnant women have been identified.A 2020 systematic review on the quality of antenatal corticosteroids for preterm birth in LMIC [14] identified substandard dexamethasone samples due to inadequate API.A separate 2020 systematic review on the quality of multiple maternal medicines in LMIC identified 34 studies, with the highest failure rates reported for ergometrine, oxytocin and misoprostol [13].A 2016 systematic review on the quality of oxytocin in LMICs identified poor quality of oxytocin samples due to insufficient API [15].Combined with the evidence presented in the current study, there is clearly cause for concern that multiple medicines used in the management of leading causes of maternal and perinatal morbidity and mortality have quality issues.
Identifying precisely where and why quality issues arise within the manufacture and distribution pathways is key to developing strategies to improve medicine quality.However, most of the studies we identified did not assess important quality parameters, particularly physicochemical assays (dissolution, disintegration and friability assays).We also could not clearly identify the cause of low quality, as sample collection processes and locations were not described in most studies.It is thus difficult to draw conclusions whether poor-quality is attributable to manufacturing issues, storage conditions or a combination of both, based on currently available evidence.No studies reported information on how medicines had been stored in the sampling setting.Given that multiple studies reported on the presence of degradants or impurities, understanding storage conditions is particularly critical to addressing systematic causes of poor-quality medicines.Future research should comprehensively assess and report on all medicine quality parameters using reference methods, to facilitate a better understanding of the root causes of medicine quality issues.Studies should ideally follow WHO survey guidelines for post-marketing surveillance assessing medicines quality [57].In addition, evaluating medicine quality from different outlets and points along the supply chain, and their current regulatory status, should also be performed.While it is acknowledged that resource capacity is limited, particularly in LMICs, we strongly encourage national regulatory authorities to implement robust pharmacovigilance and post-market surveillance programs to monitor and address poor-quality medicines, including for maternal health.

Conclusion
This systematic review identified evidence of widespread quality issues in medicines for management of HDP.These medicines impose avoidable risks to the health of women and newborns and have adverse economic implications.In order to accelerate progress towards the Sustainable Development Goals, high-quality and effective medicines need to be easily accessible and affordable, in all countries.While further research is warranted, there is a clear need for rapid improvement in the regulation, procurement, storage and quality monitoring of these medicines.

Table 2 . Characteristics and findings of studies on quality of magnesium sulphate. Study Country Income level of country Year of sample collection Pharmacopoeia / standard methods Study quality grade
HIC: High income countries, LMIC: Low and middle-income countries, LIC: Low income countries.https://doi.org/10.1371/journal.pgph.0002962.t002