New Drug Therapies for Women with Eclampsia – Impact on Prognosis as Compared to Standard Treatment: A Systematic Review of Randomized Controlled Trials

INTRODUCTION

Hypertensive disorders continue to be a major global health concern, impacting millions of pregnant women annually, and have a significant impact on maternal and neonatal mortality and morbidity. The two main spectrums of disease are pre-eclampsia (PE) and eclampsia. While PE is characterized by milder symptoms, eclampsia includes hypertensive symptoms plus impaired brain function and seizures or coma.^[1,2]

Eclampsia usually manifests as high blood pressure (BP), proteinuria, and edema, which occurs after 20 weeks of gestation.^[3,4] It affects multiple systems of the body, which account for its fatality through irreversible damage to the mother’s organs, endangering both maternal and fetal life.

Despite a global decline of 34.2% in the maternal mortality ratio (MMR) from 2000 to 2020, MMR is still a great challenge in the African region.^[5] According to the World Health Organization (WHO) (iAHO Maternal Mortality Regional Factsheet 2023), hypertensive disorders account for 22.0% of maternal mortality, which is 2^nd most common cause of death after hemorrhage.^[5]

The pathophysiology of this disorder remains obscure. The theories put forward more commonly involve vascular injury. Endothelial activation and endothelial cell dysfunction are the hallmark of PE and are, therefore, one of the most important etiopathologies.^[6]

The management of this obstetric condition involves drug treatments aiming at the rapid control of BP and prevention of severe complications until the fetus reaches an appropriate gestational age for delivery. The standard drug therapy mainly includes antihypertensives and magnesium sulfate.^[7] However, these drugs bear adverse effects and are sometimes not as effective as they are claimed to be. This is the driver for further studies to be undertaken to delineate which treatments will best prevent unfavorable outcomes related to hypertension (HTN) during pregnancy. This systematic review was conducted to identify drugs for better prevention and better treatment of the condition by providing tailor-made therapy to those suffering from the disorder. This research is not necessarily designed to find better and novel drugs but to find regimens and combinations that improve the standard tried and tested drugs currently in use. This can be achieved by combining standard drugs in use with adjuvant drugs that potentiate their effect^[8] and, in other instances, reduce the risk of systemic toxicity.^[2] Certain drugs under study may show the ability to bring about protective effects on the respective damaged organs in parturient with eclampsia. The effectiveness of the drug is expressed through levels of biological markers in those individuals.^[9] While the disease outcome is directly related to early diagnosis and management, it is obvious that more consideration should be put on those new drugs/drug combinations that are not used as standard treatment.^[10-12] This systematic review aims to explore safer and novel drugs/drug combinations with minimal adverse effects to the mother and fetus, which will cause a rapid decrease in BP, better bioavailability, and prevent life-threatening complications.

METHODOLOGY

The PubMed and PubMed Central databases were used to perform a comprehensive literature review. The Mesh terms and Boolean operators used were “Pre-eclampsia” OR “Eclampsia” AND “Drug therapy.” This study is compliant with PRISMA guidelines, ensuring transparency and adherence to recognized standards.

RESULTS

The systematic literature search performed resulted in a total of 4,360 articles, of which 4,032 were earmarked as irrelevant and excluded from the primary screening. A further rigorous evaluation and analysis of the relevant titles as well as abstracts based on both the inclusion and exclusion criteria ultimately resulted in the inclusion of 6 randomized controlled trials from the analysis of the quality assessment [Figure 1].

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Figure 1:

Inclusion of articles by (PRISMA) preferred reported items for systematic reviews. PRIMSA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

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The systematic review revealed some new drugs and new drug combinations that have proved to be beneficial in the treatment of PE and eclampsia. Table 1 depicts summary of studies, sample size and inclusion criteria. In addition, they have also each shown to have particular advantage(s) over at least one of the standard drugs currently being used [Table 2].

DISCUSSION

PE and eclampsia are often the cause of sleepless nights for many obstetricians, as these hypertensive conditions are often difficult to manage. The treatment modalities for these hypertensive conditions range from conservative lifestyle and dietary measures to aggressive pharmacotherapeutic and surgical measures. The use of drugs in treating PE is a necessity and is often a lifesaving preventative measure to retard the development of eclampsia. Magnesium sulfate is the drug most often initiated for both eclampsia and severe PE, and according to the WHO, it is the drug of choice in such conditions.^[13] Many doctors, however, disagree with the current dosing regimen thereof. A review study performed by Pratt et al. on 248 fully reviewed studies concluded that lower dosages of magnesium sulfate may be as effective as traditional therapeutic dosing. Magnesium sulfate is believed to have a high rate of catastrophic side effects such as hyporeflexia, confusion, hypotension, muscle weakness, respiratory depression, and renal insufficiency. It is thus logical that an alternate drug or class of drugs are further studied and implemented in the treatment of these hypertensive conditions, which will produce the same desired result without the negative side effects produced by magnesium sulfate.^[14]

Some of the newer drug alternatives have shown the potential to be more effective than magnesium sulfate in controlling HTN. Two strong alternatives to magnesium sulfate are dexmedetomidine and a nifedipine and phytosterol combination. The difficulty in gaining approval for such drugs is to exclude potential teratogenicity, thereby requiring intense and prolonged pharmacovigilance. Dexmedetomidine is a promising drug which may be used as an alternative to labetalol in hypertensive asthmatic patients. In a randomized control trial performed by Zhang et al., on 134 patients, it was found that both the systolic BP and diastolic BP decreased more in the interventional group (IG) receiving the dexmedetomidine as opposed to the placebo. The reduction in the urinary concentrations of β2-microglobulin, kidney injury molecule-1, and urine protein post infusion suggests that the drug has a significant reno-protective effect. The mechanism of action of dexmedetomidine is not well understood, and further studies will need to be undertaken to ensure that long-term exposure to the drug poses no harm to both the mother and unborn child.^[9] A further study performed by Yu et al. concluded that the use of dexmedetomidine in patients with gestational HTN after cesarean sections can enhance the sedative effect as well as aid in the recovery of the postpartum mothers, protect the myocardium, reduce the “stress response,” and enhance coagulation thereby promoting the use of this drug.^[15]

Another therapeutic alternative is to use traditional drugs such as calcium channel blockers, for example, nifedipine, in combination with adjuncts such as phytosterol. A randomized control trial was performed by Zhang and Feng, on 253 patients. The CG received 10 mg nifedipine tablets with a starch placebo, and the IG received 10 mg nifedipine tablets with 300 mg phytosterol capsules. The IG displayed a notable delayed time for the re-occurrence of another hypertensive crisis (8.3 ± 1.7 h as compared to the nifedipine placebo (6.1 ± 1.9 h). It was also noted that a lower dosage of the drugs was required to control the HTN in the IG. Phytosterol still poses a challenge in that its mechanism of action is unknown, and it is evident, however, that a multi-center trial in a larger center is warranted.^[8] An additional study performed by Gao et al., on phytosterol in pregnancy, with women suffering from gestational diabetes concluded that their study supported the potential clinical efficacy of phytosterol in alleviating both maternal symptoms and neonatal complications of mothers suffering from gestational diabetes. It is thus vital for more studies to be undertaken to understand the full potential of phytosterol.^[16]

A combination of magnesium sulfate and compound Danshen was trialed by Zhou et al., and the CG received a conventional treatment of 5 g of magnesium sulfate, which was dissolved in 20 mL of 5% glucose solution and was intravenously infused in a 30-min window.^[3] The IG received the additional compound Danshen injection (16 mL). The compound Danshen injection adjuvant therapy was found to optimize the clinical manifestations of S-PE and reduce systemic hypercoagulability. It was also found to improve the kidney function.^[2] It is suggested that this study should be repeated with a lower dose of magnesium sulfate as if the Danshen adjuvant can still produce similar results; despite the lowered magnesium sulfate dosage, it would reduce the likelihood of magnesium sulfate-induced side effects and could thereby be a viable option for the treatment of PE and eclampsia. A meta-analysis performed by Chen et al., on the combined efficacy of Danshen and conventional antihypertensives in the treatment of hypertensive left ventricular hypertrophy (HLVH), concluded that the antihypertensive effect of a drug combination with Danshen and conventional anti-hypertensives could be greater and more beneficial for the patients. This study further supports the notion that Danshen, in combination with magnesium sulfate, may provide a greater pharmaceutical outcome and benefit as opposed to monotherapy.^[17]

It is only after the drugs discussed above are recognized and approved by the relative bodies that the information and data provided should sensitize clinicians to the alternate possibilities available to treat PE and eclampsia. The decision to select an alternate drug should strictly be made on a case-by-case basis and should be determined by the relative indications and contraindications of the specific patient.

CONCLUSION

There are novel and promising alternatives to mono-therapeutic magnesium sulfate in the treatment of severe PE and eclampsia. These drugs are namely dexmedetomidine, nifedipine in combination with phytosterol, magnesium sulfate, and compound Danshen combinations. The use of these drugs is, however, off-label in nature and should be instituted solely on a case-by-case basis at the discretion of the physician. The prospect of a combination therapy being developed from the above drug groups is promising, and these findings should instigate further studies to provide the next generation of pharmacotherapeutic treatment protocols to combat severe PE and eclampsia.