**5. Current state of research about PE**

Research is now making its way into the subject of pregnancy and its pathologies in order to have a better understanding of physiological processes and to reduce maternal-fetal morbidity and mortality. However, despite the intentions and efforts of researchers, little is known. In the context of PE, it has been possible to trace its origin to the inadequate invasion of the trophoblastic villi on the vascular bed of the uterine spiral arteries, little is known about the cause of this inadequate adaptation of the uteroplacental vascular system [8]. Moreover, we are in complete disbelief about why some women develop PE and others do not. There is no effective diagnostic test to predict who will have PE, the best biomarkers have poor predictive power, the best chance to achieve prevention so far arises from the combination of Doppler ultrasound with some of the serum markers, which have been implemented, nevertheless, only demonstrate efficacy once the first evident changes of PE are presented, when it is no longer possible to avoid the development of the disease [9]. A real opportunity for prevention of PE would arise from a marker that would allow us to know with great certainty, which women are at risk of having PE, even before the pregnancy is carried out. The best predictive tool we have are the risk factors that have been determined by both prospective and retrospective studies, but are only able to predict 30% of women who develop PE [9], there is even a larger group of the population that develops PE with no previous risk factors. On the other hand, from the group of women who develop PE, one part shows severe PE and another group develops eclampsia, and again it is not possible for the treating doctors to determine

In women with severe PE, who present it before fetal viability, maternal stabilization is recommended before interruption of pregnancy. Once treatment is established, close monitoring is required to identify the presence of serious complications of PE. Despite efforts to treat PE, treatment is symptom-based and focused on controlling blood pressure. In regard to the time of delivery, gestational age should transfer to the maximum possible. However, in severe PE, in addition to antihypertensive treatment, termination of pregnancy is recommended if it is greater than 34 weeks. If the pregnancy is less than 34 weeks and the mother and product are stable, the pregnancy should be continued with administration of corticosteroids. Currently, there are multiple criteria for better management of PE, but the only cure for PE is termination of pregnancy. This results in a difficult decision for the physician and the mother because of

The results of medical interventions have failed to significantly decrease the morbidity and mortality of PE. The main reason for this failure could be the multifactorial origin of pathogenic processes that lead to the development of PE. Therefore, the approach for management of patients with PE is preventing its late occurrence in pregnancy. The key to prevention of PE is knowledge of the factors that trigger pathophysiological processes that culminate in the presentation of the PE. However, efforts to understand the origin of these processes are still poorly or incompletely understood. There is a lack of knowledge because the approach to study this population may be unethical compared with diseases of nonpregnant women [10]. The multifactorial origin of PE and difficulty of carrying out an investigation in the early stages of pregnancy, because it can endanger the mother and fetus, have made research difficult. Understanding the developmental characteristics of the placenta in pregnancy at high risk for PE is essential for understanding the pathophysiology and for developing strategies

who and how they evolve to more serious stages.

50 Clinical Trials in Vulnerable Populations

of prevention [8].

the psychological burden, and the social and economic morbidity [8].

There are currently 236,008 clinical trials registered in clinicalTrials.gov, from which only 3% are focused on pregnancy, and among them 6.4% are about PE. Of all clinical trials dedicated to PE, 47.9% focus on strategies to improve treatment, 22.2% of the clinical trials aim to improve the diagnosis or its establishment in the early stages, and 16.7% aim to establish the utility of new biomarkers, for both diagnostic and monitoring. Finally, only 10.7% of the clinical trials registered until February 1, 2017 are focused on the prevention of PE (**Figure 1**).

Another aspect that should be taken under consideration is that more than half of the clinical trials directed to PE are carried out in regions classified as first world such as Europe and North America, whereas research in the rest of the world only constitutes 40%, despite the fact that developing countries are the ones that bear the greatest burden of morbidity and mortality caused by this disease (**Figure 2**).

In our times, PE has a worldwide relevance and it has been increasing over the years. Clinical trials with the objective of reducing the morbidity and mortality of this pathology have also increased over time. The previous chart denotes some of the terminated trials registered in clinicaltrials.gov, many of which have certain limitations that we were able to observe (**Table 1**).

In the study titled, "l-arginine and antioxidant vitamins during pregnancy to reduce preeclampsia", there is little coherence between the objective and the design of the study. Although

**Figure 1.** Clinical trials registered until February 1, 2017. Data from: clinicaltrials.gov.

**Title Hypothesis Population Intervention Conclusions**

Women with singleton pregnancy having severe preeclampsia at 23–25 6/7 weeks of gestation

Pregnant patients with a previous history of preeclampsia in the immediate prior pregnancy

Pregnant women in 28 weeks (0 days) and 33 weeks (+4 days) of gestational age with a diagnosis of preeclampsia or superimposed preeclampsia requiring hospitalization

Women with 24–37 weeks of pregnancy with Singleton pregnancy, primiparous and primigravid diagnosis of preeclampsia

Pregnant women with a history of a previous pregnancy complicated by preeclampsia, or preeclampsia in a first degree relative, whom are deemed to have an increased risk of recurrence of the disease, were studied from 14 to 32 weeks of gestation and followed until delivery

Supplementation with: medical food-bars containing L-arginine plus antioxidant vitamins, antioxidant vitamins alone or placebo

Clinical Trials in Pregnant Women with Preeclampsia http://dx.doi.org/10.5772/intechopen.70185

> Apheresis for extracorporal removal

Aspirin 81 mg once a day orally, progesterone 200 mg twice daily

RLX030 15 μg/kg/day IV

Continuous Positive Airway Pressure Ventilation (CPAP)

for 72 h

of sFlt-1

Supplementation during pregnancy with a medical food containing L-arginine and antioxidant vitamins reduced the incidence of preeclampsia in high-risk pregnancy

53

Does not have a

Does not have a

Not enough information was provided to analyze because the study was stopped after three patients were enrolled

Does not have result

result

result

L-Arginine and Antioxidant Vitamins during Pregnancy to Reduce Preeclampsia

Usefulness of Extracorporeal Removal of sFLT-1 in women with very early severe Preeclampsia (ADENA)

Oral Progesterone and Low Dose Aspirin in the Prevention of Preeclampsia

Safety and Efficacy of RLX030 in Pregnant Women with Preeclampsia

CPAP in Preeclampsia

*Source*: Clinicaltrials.gov [11].

**Table 1.** Current state of clinical trials about PE.

To test that a relative deficiency of L-arginine, precursor of *nitric oxide* (NO) by the enzyme NO *synthase* (NOS), reduces the development of preeclampsia in highrisk pregnancies

The removal of s-Flt1 improves perinatal death in women with very early severe preeclampsia

Low-dose aspirin combined with progesterone will decrease the risk of preeclampsia in pregnant women with history of preeclampsia in a previous pregnancy

Part 1: To assess the safety and tolerability of different doses of RLX030, when given to pregnant women with preeclampsia. Part 2: To assess whether an optimal dose of RLX030 can prolong pregnancy in women with preeclampsia

To assess the effects of nasal CPAP in pregnant women (24– 37 gestational weeks) with preeclampsia

**Figure 2.** Clinical trials on PE reported by region.

it is known that the production of nitric oxide and l-arginine as the main substrate of nitric oxide synthase is involved in the pathophysiology of PE, the study design is directed at the effect of l-arginine that has on the development of PE; however, levels of l-arginine are not evaluated at any moment, neither its nitrates nor nitrites, being the reason why this design cannot help reach the hypothesis. In addition, the main inclusion criteria appeared to be having a high-risk profile for developing PE; however, high-risk factors such as diabetes, autoimmune diseases, and hypertension in pregnancy and kidney diseases are not considered as inclusion criteria, and these factors combined with a history of risk of developing PE in previous pregnancies, increase up to nine times the risk of developing PE. Another mistake that can be found in their design is noted when analyzing the main conclusion and the way the intervention was carried out, the conclusion states that the supplementation of l-arginine and vitamins reduces the incidence of PE; nevertheless, in the results it can appreciated that the group that only received the food-bar containing the vitamins did not have a significant reduction in the risk of developing PE. Meaning that the mayor contributing factor for the reduction of PE was indeed l-arginine and not the combination of l-arginine/vitamins, and these would have been more notorious if a supplementation group taking only l-arginine was added [11].

In the study titled "Usefulness of Extracorporeal Removal of sFLT-1 in Women with Very Early Severe Preeclampsia (ADENA)", at first instance we are lead to appreciate that the primary outcome of the study is about early severe PE; however, later, we appreciate that the intention is improving perinatal death as the primary outcome. The first comment worth mentioning is that using words such as "improving" in an investigation study may be to imprecise, it is better to use terms such as "reducing" for this instance. Moreover the levels of sFLT-1 are not per say an inclusion criteria for deciding whether or not to perform apheresis, even by being quantified before and after the intervention, those women with high levels of sFLT-1 could perhaps have a


**Table 1.** Current state of clinical trials about PE.

it is known that the production of nitric oxide and l-arginine as the main substrate of nitric oxide synthase is involved in the pathophysiology of PE, the study design is directed at the effect of l-arginine that has on the development of PE; however, levels of l-arginine are not evaluated at any moment, neither its nitrates nor nitrites, being the reason why this design cannot help reach the hypothesis. In addition, the main inclusion criteria appeared to be having a high-risk profile for developing PE; however, high-risk factors such as diabetes, autoimmune diseases, and hypertension in pregnancy and kidney diseases are not considered as inclusion criteria, and these factors combined with a history of risk of developing PE in previous pregnancies, increase up to nine times the risk of developing PE. Another mistake that can be found in their design is noted when analyzing the main conclusion and the way the intervention was carried out, the conclusion states that the supplementation of l-arginine and vitamins reduces the incidence of PE; nevertheless, in the results it can appreciated that the group that only received the food-bar containing the vitamins did not have a significant reduction in the risk of developing PE. Meaning that the mayor contributing factor for the reduction of PE was indeed l-arginine and not the combination of l-arginine/vitamins, and these would have been

**Figure 2.** Clinical trials on PE reported by region.

52 Clinical Trials in Vulnerable Populations

more notorious if a supplementation group taking only l-arginine was added [11].

In the study titled "Usefulness of Extracorporeal Removal of sFLT-1 in Women with Very Early Severe Preeclampsia (ADENA)", at first instance we are lead to appreciate that the primary outcome of the study is about early severe PE; however, later, we appreciate that the intention is improving perinatal death as the primary outcome. The first comment worth mentioning is that using words such as "improving" in an investigation study may be to imprecise, it is better to use terms such as "reducing" for this instance. Moreover the levels of sFLT-1 are not per say an inclusion criteria for deciding whether or not to perform apheresis, even by being quantified before and after the intervention, those women with high levels of sFLT-1 could perhaps have a greater benefit, reason why stabilizing grades at first instance could help the obstetrician make a better clinical decision. Finally, although its justifiable not using a control group, this type of design (before and after), not having a reference group, leads to a lower internal validity [11].

regarding new biomarkers and new opportunities of intervention emerge every year, but these are not implemented by the treating physicians. Moreover, clinical practice guidelines are lagging too, and many years pass before a new intervention reaches the level of recommendation within them. On the one hand, this occurs because the information that is generated seems to be isolated and fragmented, there is no body or work team or expert committee that focus their efforts on trying to solve the problem or on generating a line of research on the subject. Another part of the transforming knowledge problem is that for this to be carried out it is necessary that the information obtained may be applicable to different populations at different times and with different characteristics, this is very complex to achieve in the first place because, as mentioned previously, there is no focus group to this and separated efforts generate a bias in the study population. Another bias that impedes transfer is that the risk factors presented by each population are different in the developed countries than those in the developing world, so information generated on the one side is not necessarily applicable in other parts of the world. Because the origin of PE is not well understood, the approaches with which the different studies are developed differ, while some may determine that the cause is oxidative stress, some others may argue that the cause is genetic. The truth is that so far it is considered multifactorial and because of this the international guidelines are more discreet about which recommendations to accept, in the sense of being able to verify which actions will

Clinical Trials in Pregnant Women with Preeclampsia http://dx.doi.org/10.5772/intechopen.70185 55

Finally, one of the most worrying aspects that delay the transfer of knowledge is the lack of medical update on the subject. A very obvious example is that in practice, physicians do not intentionally seek pregnancies with a high risk of PE, and when a patient is classified with high risk, the first action of the doctor is an expectant management, without any intervention, although in the guidelines of clinical practice the administration of acetylsalicylic acid, calcium, and l-arginine is recommended, this happens because evidence of acetylsalicylic acid's efficacy in reducing the risk is contradictory, while calcium intake is reserved for those women with low risk and low calcium intake, and l-arginine, although it is part of the

Other evidence in the lack of management of the subject in some specialists is the lack of communication they generate with patients who are at high risk. Patients are not informed of their situation and expectant management "poor surveillance" continues even after the patient develops PE, which is when the symptomatic management begins, and it seems that the physicians are waiting for a complication to occur, to make the decision of taking a more active management. It is true that during the 1st weeks of the PE, there are not many recommendations, and that most focus on the final stages in which fetal viability can be achieved, but this same reason should be what drives medical doctors to have a closer monitoring in research opportunities and new information to improve the outcome of the pregnancy, remembering that once PE is presented, there is no curative treatment, beyond the interruption of pregnancy. Efforts should be directed at preventing the occurrence of PE or, failing at that, occur-

have an evident weight in clinical practice.

Canadian guide, no dosage or time is specified.

ring late in pregnancy.

In the study titled "Oral Progesterone and Low Dose Aspirin in the Prevention of Preeclampsia", the main inclusion criterion is having a history with preeclampsia. Nevertheless, other factors of high risk were not taken account. Even though the study propounds that a deficiency of progesterone could lead to PE and in consequence, supplementation with progesterone could reduce the incidence of PE, serum values as an indicator to identify patients whom could benefit with progesterone supplementation were not taken into account. The comparison between before and after instead of vs the placebo group is also an inconvenient [11].

In the study titled "Oral Progesterone and Low-Dose Aspirin in Preeclampsia Prevention," the main inclusion criterion is the antecedent of PE in previous pregnancies; however, as in the previous study, other factors that increase the risk are not taken into account. The study assumes that a deficiency of progesterone could be the cause of PE, this argument seems to be the rationale to reduce the incidence of PE using supplementation with progesterone; but in the study, they did not take serum values in consideration as a marker to indicate which patients could benefit from supplementation. This study, as the previous one, also lacks the comparison against a placebo group, creating the same limitations [11].

In the study entitled "Safety and Efficacy of RLX030 in Pregnant Women with Pre-Eclampsia" proposed by the company NOVARTIS did not have sufficient information to perform an analysis, because of premature termination of the study [11].

In the study entitled "CPAP in Preeclampsia", the main objective is the evaluation of fetal wellbeing using nasal continuous positive airway pressure (CPAP) as a basis to increase fetal oxygenation; however, monitoring fetal movements is a scarce strategy to evaluate fetal well-being and it could be enhanced, according to the advances in fetal medicine to allow us to get closer to knowing the well-being of the fetus. The study did not make a distinction on the severity of PE, and if a clinical benefit of using CPAP is demonstrated, a distinction on the severity might be useful for clinical decisions. Therefore, the rationale to use CPAP is not clear [11].

In several studies, narrowing gestational age as inclusion criteria perhaps increases internal validity; however, the results cannot be extrapolated to other groups [11].

It is worth noting that the protocols registered in clinical trial go through variations during the study, which go unnoticed.
