Retrospective Assessment of the Use of Pharmacotherapeutic Agents in Pregnancy with Potential Impact on Neonatal Health

This study focuses first on the role of the clinical pharmacist in Slovakia as a specialist who can advise or provide a suggestion of optimisation of pharmacotherapy to physicians who are managing a patient's pharmacotherapy. After that, with the consent of physicians, the pharmacotherapy can be optimised. Thus, the clinical pharmacist has an essential place in the hospital system (Göböová, 2016). The clinical pharmacist is contributing to the minimisation of the risk and unwanted adverse effects and maximisation of the effectiveness of treatment in the given patient (Vlček et al., 2010). The clinical pharmacist is an important part of hospital counselling and informative activity for a specialised pharmacotherapeutic group of patients during pregnancy and lactation.

Clinical pharmacists in the hospital-clinical sector connect health care workers, including physicians, nurses, hospital management, and others. They can provide a view on pharmacotherapy by more detailed knowledge about therapeutic agents and mechanisms. The clinical pharmacist also provides an assessment of the risk of medications, suggests adjustments of pharmacotherapy, and assists in selecting the appropriate medical form and method of administration at the physician's request. The final decision about the patient's ongoing treatment has a physician in the appropriate specialization.

According to Little (2006), the pharmacist must consider different factors and aspects that can affect the health status of the mother, but also the foetus or newborn. Health care professionals who most frequently ask the clinical pharmacist for drug-risk assessment in pregnant patients are clinical geneticists and gynaecologists. As referred to by Göböová (2016) and Sachdeva et al. (2009), pharmacotherapy during pregnancy and lactation is one of the riskiest therapeutic procedures and presents a special concern. Physicians have to weigh the risks to the foetus and at the same time assess the risks to the mother if the therapeutic agents are not continuously used.

The clinical pharmacist must cope with an insufficient number of informative sources because patient information leaflets (PILs) and, in some respects the Summary of Product Characteristics (SmPC) contain basic information, explaining that given therapeutic agents are not appropriate for administration to patients during pregnancy and lactation. Thus, the clinical pharmacist usually relies on national or foreign teratology information centres, professional publications, retrospective studies, and summarized casuistic or scientific medical journals (Stephansson et al., 2017).

As mentioned by Schaefer et al. (2015), despite the number of new pharmaceutical products constantly increasing, their impact on maternal or foetal health remains unknown due to ethical reasons or the impossibility of clinical trial testing in pregnant women. In the case of drug-risk consultation with the patient, an individual approach must be used. As a recent study (Göböová, 2016) explained, the most common clinical pharmacist's challenge is the situation when the patient had an unexpected pregnancy but was already drug-exposed. There can also be a situation when the patient is considering a planned pregnancy or has consciously used drugs because of chronic or acute illnesses.

Clinical pharmacists should be equipped with broad-spectrum knowledge, mainly from the sphere of pharmacology and other fields, because there are, first of all, changed pharmacokinetics of the administered drug, based on altered maternal physiology (Mattison, 2013). As Giacoia and Mattison (2009) described, drug pharmacokinetics is changed on all levels from absorption up to elimination. On the other hand, experimental evidence proves specific receptor alternations during pregnancy on the level of pharmacodynamics.

Knowledge about structural and physiochemical properties regulating drug transfer is essential for the clinical pharmacist. The placenta allows fat-soluble therapeutic agents to cross more easily than water-soluble agents; afterward, the placenta contains efflux transporters that might prevent the substantial transfer of substances to the foetus and therefore lower the risk of fetotoxicity. Other systems participating in drug transfer are the yolk sac, blood–brain barrier, and foetal liver (which is able in the third month to metabolise therapeutic agents via oxidation processes) as explained by Schaefer et al. (2015).

A retrospective observational study was performed based on patient data from Teaching Hospital Nitra. Twenty-two anonymous adult female patients of different age categories were included in the study in the time frame of 24 months, from January 2015 through December 2016. These adult female patients were chosen for the study based on the inclusion and exclusion criteria. All these patients consulted on their medication with the clinical pharmacist to optimise their pharmacotherapy. Inclusion criteria and exclusion criteria determined the selection of appropriate patients. Inclusion criteria were as follows: sex, female; 18 years of age or older; pregnancy, ongoing, planned, or unknown; status of medication treatment, begun, interrupted, or finished; stage of pregnancy, first, second, or third trimester or time of conception; evidence in the clinical pharmacist medical documentation; and assessment of pharmacotherapy of the patient by a clinical pharmacist. Of the total of 40 patients, 18 patients were excluded for the following reasons: not present or missing data about pharmacotherapy, about the outcome of the newborn, or patients did not want to provide information about the outcome of the newborn. The study was carried out thanks to the cooperation of the clinical pharmacist in the clinical-hospital sector. We observed various pharmacotherapeutic outcomes, but most important, we were focusing on the measures of health condition of the newborns, which could be healthy newborn, illness of the newborn, any congenital defect or malformation (where we focused on sex, weight, and additional data about the newborn) and subsequently spontaneous abortion and unspecified information about the newborn. Unspecified information means that the outcome of the newborn was not specified in the medical documents. It was not clear if the patient had a spontaneous abortion or there was an ongoing pregnancy, so the information about the outcome of the newborn was not complete, but the patient had fulfilled inclusion criteria. Based on a foetal risk assessment of used therapeutic agents from SmPC, basal foetal and neonatal risk assessment (Briggs et al., 2017), and recommendations and related human past reports and supporting evidence studies, drugs were divided into two groups: confirmed foetal risk drugs and negative (nonconfirmed) foetal risk drugs. All patient data were processed for professional purposes while maintaining an absolute level of anonymity. The ethical review process was done by the Ethics Committee, applying the principles of major international documents concerning human rights, patients’ rights, and patient safety. The Ethics Committee works independently in its decision-making. The Commission considered ethical issues. The Ethics Committee verifies patients’ anonymity, compliance with GDPR law, the acceptability of the project and study, and respect for patient integrity.

Data from 22 adult female patients showed that the average age of patients was 32 years old. Of the 22 patients, 31.8% took one drug, 36.3% took two drugs, and 31.9% took more than two drugs (to a maximum of six). Usage of more than two drugs was rarer; the highest number of drugs used was six (9.1%). Patients most commonly used therapeutic agents during the first trimester (81.8%) and then preconception (9.1%). Afterward, between the first and second trimester, it was 4.5%. The stage of pregnancy for one patient was not known. Among the 22 pregnancies, 2 patients had a spontaneous abortion.

Fig. 1 describes the most frequently used therapeutic agents by a single patient. The most frequently used therapeutic agents according to the Anatomical Therapeutic Chemical (ATC) classification system (if each patient could have used more than one therapeutic agent) were agents for the treatment of the nervous system (25.5%), with dominating groups of N06 psychoanaleptics (35.7%) and N02 analgesics (28.6%). the second most used therapeutic drug category was anti-infectives for systemic use (23.6%), mostly J01 antibacterials for systemic use (92.9%). The third most used therapeutic drug category consisted of agents for the treatment of the respiratory system (14.5%) as R03 drugs for obstructive airway diseases (37.5%) and in equal representation with R05 cough and cold preparations (37.5%).

Figure 1

Fig. 2 represents the results of measures of health conditions of the newborns after their mothers were exposed to side effects of therapeutic agents. In most of the cases (16, 73%), newborns were healthy. Spontaneous abortions represented 2 cases (9%), and 2 cases involved illness of the newborns (9%). One case contained unspecified information about the newborn; one newborn had a congenital defect or malformation.

Figure 2

Fig. 3 provides a ratio comparison of therapeutic agents with confirmed foetal risk and negative (nonconfirmed) foetal risk. Results are that in the majority of both kinds of therapeutic agents (with confirmed and nonconfirmed foetal risk), the main outcome was a healthy newborn. In the case of therapeutic agents with confirmed foetal risk, in 18 cases the outcome was a healthy newborn (64.3%), in 2 cases the outcome was illness of the newborn (7.1%), in 2 cases the outcome was a congenital defect or malformation (7.1%), in 2 cases the outcome was spontaneous abortion (7.1%), and in 4 cases the outcome was unspecified information about the newborn (14.3%). In the case of therapeutic agents with negative foetal risk, in 22 cases the outcome was a healthy newborn (81.5%), in 2 cases the outcome was illness of the newborn (7.4%), there were no cases of congenital defect or malformation, in 1 case the outcome was spontaneous abortion (3.7%), and in 2 cases the outcome was unspecified information about the newborn (7.4%). Despite use of drugs with confirmed foetal risk or negative (nonconfirmed) foetal risk, most health outcomes were healthy newborns.

Figure 3

It was interesting that despite the patients using agents with confirmed foetal risk, in a majority of cases they had healthy newborns, which means, as the literature states, that there must be protective and defence systems (metabolic and excretion systems) that are still unknown. Despite the fact that sometimes a higher number of therapeutic agents are used during pregnancy, and it leads to a few disorders observed in the postnatal period, the foetus or newborn have high-probability repair systems. Still, very little is known about the transport of substances in the early phases of pregnancy and detoxification of xenobiotic substances (Schaefer et al., 2015). As Göböová et al. (2016) stated, clinical pharmacists can reduce unreasonable terminations of pregnancies and therefore indirectly provide higher chances for healthy newborns (including risks). There are different factors that protect an embryo or foetus. Usually, we can find information about the role of the placenta in relation to the protection and selectivity of drug transfer. However, the embryo or foetus can be protected by additional factors such as early embryonic structures, foetal defence mechanisms against oxidative stress, and the foetal lymphatic system.

An overview of therapeutic agents with confirmed foetal risk and their outcomes is presented in Table 1. In creating Table 1, we were aware that the risk of medication during pregnancy depends on dosing, duration of treatment, and stage of pregnancy during medication use. SmPC of therapeutic agents for Slovakia was used.

The study deals with the retrospective pharmacotherapeutic assessment of treatment during pregnancy. By carrying out a literature search from available articles and professional books, using the latest findings from published studies, it was possible to create an overview of the foetal risk of therapeutic agents in 22 women patients, despite the fact that at the present time, there is very limited information concerning the risks of drug use during pregnancy mainly in the PIL and SmPC.

During our study, each mother gave birth to only one newborn. In most cases, healthy newborns were born after the patients were exposed to therapeutic agents. The number of healthy newborns was 16 out of a total of 22 newborns. In the group of therapeutic agents with confirmed risk, the negative effect on the newborn's health was clinically manifested in norethisterone acetate, valproic acid, interferon β-1a, methylprednisolone sodium succinate, monohydrate sodium salt of metamizole, and budesonide. Spontaneous abortion occurred after using norethisterone acetate and valproic acid. Norethisterone is a synthetic oral progestin. During pregnancy, an observed increased risk of malformation occurred with use of norethisterone. Causal relationships and outcomes between usage of norethisterone during pregnancy and spontaneous abortion were not described (Briggs et al., 2017). For valproic acid usage during pregnancy, minor and major anomalies are described in the literature. Minor congenital abnormalities, intrauterine growth restriction, neural tube defects, and minor facial defects were reported. Intrauterine growth restriction is connected to perinatal mortality and mortality (Peleg et al., 1998; Briggs et al., 2017). Birth defects (unspecified) were present after usage of interferon β-1a and methylprednisolone sodium succinate. Spontaneous abortions were reported in relation to interferon β-1a use, which cannot be confirmed due to lack of details; however, there was observed an abortifacient effect in monkeys (Briggs et al., 2017). Corticosteroids have been shown to be teratogenic in animal species when given in doses equivalent to the human dose (State Institute for Drug Control, 2018d). Illness in the of a heart murmur was present after the use of monohydrate sodium salt of metamizole. According to a prospective follow-up study, including more than 100 women treated with metamizole in the first trimester, no increased risk for major congenital malformations was observed. The use of pyrazolone compounds can lead to hematologic adverse effects (Schaefer et al., 2015). Another illness, Wilm's tumour, was present after use of budesonide. Unspecified information about the newborn was observed in four cases after using prednisone, allopurinol, nadroparin, and fluvastatin. Reports described that usage of budesonide was connected to a small risk of cardiac defects and orofacial clefts (Briggs et al., 2017). Our study aimed to study the health outcomes of newborns after their mothers (patients) used therapeutic agents during pregnancy. However, during this study, genetic predisposition and past diseases on the mother's side were not known to us, and these factors could affect the final health outcomes of the newborns. We worked mainly with the pharmacotherapeutic data of therapeutic agents used on the maternal side.