**3. Fetal well-being in the clinical trial**

**1. Introduction**

46 Clinical Trials in Vulnerable Populations

to the therapeutic interventions.

Preeclampsia (PE) is the leading cause of preterm birth by medical indication when associated with premature detachment of placenta normoinserta, and IUGR is associated with high perinatal morbidity and mortality and long-term sequelae. It has been described that standardization in the management of health services and the use of clinical practice guidelines is associated with a reduction in adverse outcomes, and a fundamental part of the management of severe PE includes a complete evaluation of the mother and the fetus. Despite the advances in medicine, the frequency of this syndrome has not changed, and globally its incidence ranges between 2 and 10% of pregnancies. The World Health Organization (WHO) estimates that the incidence of PE is seven times higher in developing than in developed countries (2.8–0.4%). In Mexico, it is estimated that PE is a major cause of maternal and perinatal morbidity and mortality. In Jalisco alone, maternal deaths increased to 57.14% from 2011 to 2014, placing this state in fourth place at the national level in terms of maternal deaths, during 2015 [1]. Because it is a heterogeneous associated idiopathic syndrome to endothelial damage, so far there is no effective treatment that reduces the morbidity and mortality of this pathological entity, so it is necessary to reinforce prevention. In this area, only the use of calcium supplements and acetylsalicylic acid (ASA) appears to be a recommendation, albeit with controversial results [1, 2].

The main problem of PE is threefold, the diagnostic difficulty, the complicated interrelationship of the pathophysiological processes, and the vulnerability of the maternal-fetal binomial

There are various concepts about the characteristics of vulnerable populations; however, it is generally accepted that a vulnerable group is one whose ability to protect their own interest or grant their consent is physically, psychologically, or socially compromised. Since the development of ethical principles in research, children, psychiatric patients, prisoners, and pregnant women have been included in this group; however, in recent years it has been intended to remove pregnant women from this group. The National Institutes of Health (NIH) through the Office of Research on Women's Health recommended as early as 2010 that pregnant women should be considered as a scientifically complex rather than vulnerable group, this being for the reason that this group has the same capacity and autonomy for decision making as its nonpregnant counterparts, including the decision of whether or not to participate in a clinical trial [3].

Scientific complexity arises from the special physiological conditions of pregnancy and from the ethical considerations of the balance between maternal well-being and fetal well-being.

Pregnancy is accompanied by important physiological changes and their knowledge is an element of great value for the proper management of the obstetric patient. Practically, all the body's system of the pregnant woman is adapted to house the product, among them are changes at the ocular, musculoskeletal, skin and mucous, hepatic, hematological, renal, and gastrointestinal levels. The most relevant changes occur at the uterine level, systemic vascular

**2. Pregnant women, scientifically complexed population**

When deciding that the study population is the group of pregnant women, the first ethical criteria that need to be reviewed are those aimed at the protection of the fetus. Generally, investigations of pregnant women involving an intervention or experimental procedure such as in PE cases, should not expose the embryo or fetus to a greater risk than the minimum, except when the use of the intervention or procedure is justified for saving the life of the mother. However, in addition to a deep and sufficient knowledge of the intervention that is proposed to apply, there is no strategy to evaluate during the course of research the side effects on the product. Although maternal-fetal medicine is currently a fact, with several diagnostic imaging and biochemical resources, with established therapeutic procedures, there is no consensus on what tests are necessary to perform and monitor the product during investigations in pregnant women. Even experts do not dare to indicate any fetal diagnostic procedure, within the clinic in the management of pathological pregnancies, but it is at the discretion of the attending physician the use of some diagnostic or therapeutic techniques [6].

that in PE the treatment consists of the interruption of pregnancy, to be able to prolong it until reaching the fetal maturity, becomes one of the most difficult aspects of the management to avoid the fetal morbidity-mortality, reason why it is to make sure that the fetus

Clinical Trials in Pregnant Women with Preeclampsia http://dx.doi.org/10.5772/intechopen.70185 49

Although these tests and diagnostic interventions are the most used in the clinic, the amount of imaging tests, serum markers, and procedures with maternal-fetal medicine is higher; however, many of the tests have not shown their value, they could be useful and applicable reason why they require to be studied, especially those that allow predicting the presentation of complications or diseases such as PE. Among the currently available tests are the evaluation of both fetal DNA and the cells that make up the placenta, even in an experimental way, it is possible to attenuate or increase gene expression through miRNAs, not only for diagnostic

The American Congress of Obstetricians and Gynecologists states that the evaluation of fetal well-being may be appropriate for pregnancies with an increased risk of fetal involvement; however, there are no comprehensive trials demonstrating the benefit of all tests and their potential indications. On the other hand, experts recommend carrying out tests of fetal well-

As we can see that there are no specific guidelines on how to evaluate fetal well-being during pregnancy routinely in the clinic, and this deficiency is translated into clinical research with pregnant women. As mentioned before, although one of the principles of research in pregnancy is to maintain the integrity of the product, there are neither guidelines nor recommendations on which tests to apply and when to ensure the safety of the fetus. From the above, we can infer that most clinical trials involving pregnant women have not been able to guarantee or know with certainty the fetal well-being. So how is it possible to monitor fetal well-being in a clinical trial? How can we evaluate adverse effects on the product? And if there is no strategy to assess at least fetal well-being, is it ethical to allow the participation of pregnant women in clinical trials? It is up to the researcher to decide the degree of safety with which he plans to conduct his research, and in the absence of additional tests to ensure fetal well-being, using those available is the most reasonable. However, we should not be satisfied with the analysis of the structural function to guarantee the innocuousness of an intervention, it is necessary to find strategies that in fact allow to evaluate not only the welfare, structural integrity, and fetal vitality, but also to value the whole range of possible adverse effects, both acute and chronic, that may be occurring as a result of new pharmacological interventions or procedures.

Pregnancy is a physiological condition inherent in almost all species and life; however, it is one of the lesser known states and a field of research that just begins to grow, because at the beginning of research with pregnant women, a series of events occurred that negatively

counts with pulmonary maturity to resist extrauterine life has become essential.

purposes, but also for possible therapeutic applications in the future.

being in cases of diabetes, uterine growth restriction, and hypertension [7].

**4. Clinical research in women pregnant with PE**

marked research in this population.

There are six most generalized methods to know and evaluate fetal well-being [7]:


that in PE the treatment consists of the interruption of pregnancy, to be able to prolong it until reaching the fetal maturity, becomes one of the most difficult aspects of the management to avoid the fetal morbidity-mortality, reason why it is to make sure that the fetus counts with pulmonary maturity to resist extrauterine life has become essential.

product. Although maternal-fetal medicine is currently a fact, with several diagnostic imaging and biochemical resources, with established therapeutic procedures, there is no consensus on what tests are necessary to perform and monitor the product during investigations in pregnant women. Even experts do not dare to indicate any fetal diagnostic procedure, within the clinic in the management of pathological pregnancies, but it is at the discretion of the attend-

**1.** Maternal evaluation of fetal activity. It consists of the count by the mother of the number of times fetal movement occurs. Although the fetal movement count is a recommendation that is made to every pregnant woman, there is no cutoff point when abnormal movement is considered abnormal, some clinicians mark the alarm in less than 10 fetal movements perceived per day, others when no movements are perceived within 2 h. This form of assessment of fetal well-being presents a false-positive rate, since it depends on the subjectiv-

**2.** Test without stress. It consists of the evaluation of fetal heart rate in relationship to uterine contractions. Although it has a low false-negative rate (0.19–1%), its high rate of false positives (55%) makes it a test with minimal benefits, and its counterpart, the stress test, in which it is administered by infusion intravenous oxytocin, is contraindicated in high-risk situations.

**3.** Biophysical profile. It is a test composed of the evaluation of five parameters, fetal heart activity, fetal respiratory movements, fetal thick movements, muscle tone, and volume of amniotic fluid. Although its false-negative rates are very low (0.07%), its false-positive rate is only lower than that of the stress-free test, and has not shown any difference in terms of fetal death, cesarean indication, and under Apgar score. In addition to being a dependent operator test, factors that may alter outcomes include hypoxemia, gestational age, steroid administration, magnesium sulfate administration, and labor; five factors that occur fre-

**4.** Modified biophysical profile. It is the combination of the stress-free test with the biophysical profile. Although it requires less time and experience for its realization, makes its result more reliable, its false-positive and -negative rates are similar to the two tests separately.

**5.** Fetal Doppler ultrasound. The evaluation consists in measuring by ultrasound the velocity of blood flow in the fetal vessels, usually the umbilical artery. Out of all of the above, Doppler has been evaluated with the most rigorous clinical trials and although it does not show a benefit in terms of fetal death in high-risk pregnancies, it has become an effective test in the reduction of fetal morbidity and mortality in high-risk pregnancies, being this an indication for its use. The use of Doppler in pregnant women with high risk of PE can be a predictive tool combined with serum biomarkers; this strategy is still being validated but promising.

**6.** Evaluation of fetal lung maturity. It consists the evaluating the presence of surfactant factor in the amniotic fluid. It is a useful evaluation when it is necessary to determine the best time to interrupt the pregnancy when the risk of continuing it is greater. Due to the fact

ing physician the use of some diagnostic or therapeutic techniques [6].

ity of the mother.

48 Clinical Trials in Vulnerable Populations

quently in pregnant women with PE.

There are six most generalized methods to know and evaluate fetal well-being [7]:

Although these tests and diagnostic interventions are the most used in the clinic, the amount of imaging tests, serum markers, and procedures with maternal-fetal medicine is higher; however, many of the tests have not shown their value, they could be useful and applicable reason why they require to be studied, especially those that allow predicting the presentation of complications or diseases such as PE. Among the currently available tests are the evaluation of both fetal DNA and the cells that make up the placenta, even in an experimental way, it is possible to attenuate or increase gene expression through miRNAs, not only for diagnostic purposes, but also for possible therapeutic applications in the future.

The American Congress of Obstetricians and Gynecologists states that the evaluation of fetal well-being may be appropriate for pregnancies with an increased risk of fetal involvement; however, there are no comprehensive trials demonstrating the benefit of all tests and their potential indications. On the other hand, experts recommend carrying out tests of fetal wellbeing in cases of diabetes, uterine growth restriction, and hypertension [7].

As we can see that there are no specific guidelines on how to evaluate fetal well-being during pregnancy routinely in the clinic, and this deficiency is translated into clinical research with pregnant women. As mentioned before, although one of the principles of research in pregnancy is to maintain the integrity of the product, there are neither guidelines nor recommendations on which tests to apply and when to ensure the safety of the fetus. From the above, we can infer that most clinical trials involving pregnant women have not been able to guarantee or know with certainty the fetal well-being. So how is it possible to monitor fetal well-being in a clinical trial? How can we evaluate adverse effects on the product? And if there is no strategy to assess at least fetal well-being, is it ethical to allow the participation of pregnant women in clinical trials? It is up to the researcher to decide the degree of safety with which he plans to conduct his research, and in the absence of additional tests to ensure fetal well-being, using those available is the most reasonable. However, we should not be satisfied with the analysis of the structural function to guarantee the innocuousness of an intervention, it is necessary to find strategies that in fact allow to evaluate not only the welfare, structural integrity, and fetal vitality, but also to value the whole range of possible adverse effects, both acute and chronic, that may be occurring as a result of new pharmacological interventions or procedures.
