Patients and methods: In this descriptive, cross-sectional, retrospective study, a total of 47 pregnant women (mean age: 34.0±5.5 years; range, 19 to 41 years) who were admitted to the TIS of Dokuz Eylul University were included between January 2014 and December 2016. Demographic characteristics, types of the CVMs, concomitant medication and/or substance use, medical and obstetric histories of cases, and maternal and neonatal outcomes were evaluated.

Results: The most commonly used drugs were beta-receptor antagonists. The mean gestational age at the time of delivery was 35.9±8.2 weeks and 42 infants (89.4%) were healthy. Five pregnancies (10.6%) ended in miscarriage or elective termination. No malformation was found in healthy live newborns.

Conclusion: The use of CVMs during pregnancy remains as a challenging issue, as their potential effects on the developing fetus are not fully known. Based on these study results, it is difficult to determine safety of CVMs during pregnancy and establish a causal relationship between maternal/neonatal outcomes and CVMs exposure.

In developed countries, cardiac diseases are the most common causes of maternal mortality during pregnancy. According to the epidemiological studies, approximately every year 0.2% of all pregnant women die from cardiac reasons.[1-4] Additionally, in the United States, 11% of the maternal deaths during pregnancy are caused by cardiac diseases.[5] Physiological changes in pregnancy may adversely affect the prognosis of an existing cardiovascular disease and may alter the effects of medications which affect the cardiovascular system. Also, the effects of the cardiovascular medications (CVMs) on the fetus are not fully known. It is also an undeniable fact that ethical concerns limit the controlled studies on this subject. Thus, the data regarding the use of CVMs during pregnancy and their effect on pregnancy outcomes are limited in Turkey.

In the present study, we aimed to evaluate the demographic characteristics of pregnant women referred to the Teratogenicity Information Service (TIS) during pregnancy and to identify the characteristics of the CVMs exposures and the pregnancy outcomes.

The data of the pregnant women included in the study were obtained from the registration forms filled out during the initial admission to TIS. The data collected from the registration forms were as follows: demographic data (age, educational status, presence of consanguineous marriage), medical, family and obstetric history (gestational week, last menstrual period, number of pregnancies, number of live/stillbirths in previous pregnancies, presence of anomalies in previous pregnancies), and CVMs and exposure characteristics (name, content, dose, total amount, and duration). The gestational week was calculated according to the ultrasound data or the last menstrual period. To obtain the verbal consent and investigate the pregnancy outcomes and confirm the data, a phone interview was conducted with each mother. In addition, data related to the pregnancy outcomes (term birth, preterm delivery, miscarriage, elective termination, stillbirth, baby healthy, presence/absence of anomaly) and possible complications during pregnancy were obtained by phone interviews. Pregnant women who did not give a verbal consent were excluded from the study. Pregnancy outcomes were classified using the International Classification of Diseases 10th revision (ICD 10) definitions of World Health Organization (WHO).[6] Elective termination was defined as the voluntary abortion, miscarriage as a pregnancy loss before 22 completed weeks of gestational age, stillbirth as the birth with no signs of life after 22 completed weeks of gestational age, and preterm birth was defined as the birth before 37 completed weeks of gestational age.[6]

Statistical analysis
Statistical analysis was performed using the IBM SPSS for Windows version 22.0 software (IBM Corp., Armonk, NY, USA). Descriptive data were expressed in mean ± standard deviation (SD) or median (min-max) for continuous variables and in number and frequency for categorical variables. In the comparison of the two groups, the chi-square (c2) test was used for categorical data. The Fisher’s exact test was used, when the c2 assumption was not met. A p value of <0.05 was considered statistically significant.

Table 1: Maternal demographic and obstetric characteristics

There was no significant relationship between the presence of consanguineous marriage and pregnancy outcomes (χ²=0.199, p=0.655) (Table 2).

Table 2: The association between some properties of pregnants and pregnancy outcomes

When the presence of chronic disease was evaluated, it was found that 89.4% (n=42) of pregnant women had an existed chronic disease and the most commons were hypertension (HT, 28%), diabetes mellitus (DM) and hypothyroidism (11.9%, Figure 1). No statistically significant relationship between presence of a chronic disease and pregnancy outcomes was found (χ²=0.032, p=0.858) (Table 2). The characteristics of illicit drug/alcohol use, radiation exposure or smoking are presented in Table 1.

Figure 1: Chronic diseases of the pregnants.

Approximately one third of pregnant women (29.8%, n=14) used CVMs alone and 70.2% (n=33) reported concomitant medicine exposures (Table 3). The most frequently exposed concomitant medicines were central nervous system drugs (30.3%) and analgesics (18.2%). The proportion of the mothers who used only one group of CVMs and more than one group CVMs were 76.6% (n=36) and 23.4% (n=11), respectively (Table 3). There was no significant difference between using one or more than one group of CVMs and pregnancy outcomes (χ²=2.787, p=0.095).

Table 3: Distribution of the medication exposures

The most frequently exposed CVMs were beta adrenergic receptor antagonists (beta-blockers), diuretics, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers (CCB), angiotensin receptor blockers (ARB), antiaggregants, antilipidemics and antiarrhythmics (Table 2). There was no statistically significant difference between groups of CVMs exposed during pregnancy and the termination of pregnancies (p>0.05).

When gestational outcomes were examined, the mean gestational week at delivery was 35.9±8.2 weeks. Of all 47 pregnancies with CVMs exposure, 42 (89.4%) pregnancies resulted in live births. Three (6.4%) pregnancies ended in elective termination and two (4.3%) pregnancies ended in miscarriage (Table 4). No malformation was detected in any of the live births. Neonatal jaundice developed in four (9.8%) infants and one (2.1%) infant needed incubator care.

Table 4: Properties of the cases ended in miscarriage or elective termination

There was no statistically significant difference between pregnancy outcome and educational status, substance use of radiation exposure during pregnancy (p>0.05). It is stated that while the 21 (44.7%) pregnant women’s age was under 35 years, the 26 (55.3%) pregnant women’s age was over 35 years. There was no significant difference between maternal age and the termination of pregnancies (χ²=0.140, p=0.308) (Table 2).

Cardiac diseases are complicated by approximately 1% of all pregnancies.[9] Pregnant women with or without underlying cardiovascular disease may need to use CVMs due to the physiological changes during pregnancy. This need may be caused by worsening of an existing disease or by a newly developing condition. In general, medications used to treat cardiovascular conditions are antihypertensives, diuretics, antiarrhythmics, anticoagulants and antilipidemics. Moreover, CVMs are preferred in other indications such as migraine, tremor, hyperthyroidism, and anxiety disorders.[9] However, the effects of CVMs on the developing fetus have not been fully understood, yet. Pregnant women need a careful assessment and counselling for CVMs use and their maternal/fetal effects, as well as expert cardiac care in pregnancy. Teratogenicity Information Services are specialized units providing information on the use of medication/ substance during pregnancy and lactation period. The TIS of Dokuz Eylul University is a regional unit dedicated to provide information about medication/ substance use during pregnancy and/or lactation period since 2011.

Epidemiological data on CVMs exposures during pregnancy are limited. In a study carried out in Germany on drug prescriptions in pregnancy, CVMs accounted for 17% of the medicines prescribed during pregnancy.[10] In another study conducted by Demir et al.,[11] CVMs were responsible for 9.5% of all exposures among the pregnant women admitted to TIS. Göker et al.[12] also reported that the use of CVM ratios were 1.14% and 8.17% in a study evaluating pregnants admitted to two reference hospital in our country. In this study, this rate was 12.6% of the patients applied to the TIS of our institution.

The increasing prevalence of women with adverse pregnancy outcomes (stillbirth, fetal malformations or abortus) due to the increasing maternal age of first pregnancy remains as a challenging issue. Advanced maternal age, particularly over 35 years of age, poses a greater risk of pregnancy complications.[13] Almost 7% of stillbirths are attributed to advanced maternal age (>35 years) worldwide. Also, adolescent pregnancy (<16 years) is associated with an increased risk of adverse pregnancy outcomes.[1,14] In this study, the mean age of pregnant women was 34.0±5.5 years. Additionally, it is noteworthy that four (80%) of five pregnancies ended in miscarriage or elective termination were older than 35 years old (31 to 40 years).

The pregnancy termination rates in consanguineous marriages may be higher due to the increased risk for recessively inherited congenital diseases.[14] In a study carried out in our country, the rate of consanguineous marriage was found to be 12.7%.[11] In this study, the rate of consanguineous marriage was found as 6.4% and all pregnancies with consanguineous marriages resulted in a healthy infant.

On the other hand, the presence of chronic diseases during pregnancy also poses a risk for adverse pregnancy outcomes. The most common chronic diseases in pregnant women are epilepsy, hypertension, diabetes mellitus, psychiatric diseases, and thyroid dysfunctions.[15] In this study, approximately 90% of the mothers had a chronic disease, consistent with the previous reports, and hypertension, diabetes mellitus, and hypothyroidism were the most common diseases. Furthermore, 60% of the mothers whose pregnancies ended in miscarriage or terminated electively had an underlying maternal chronic disease such as hypothyroidism, hypertension, or diabetes mellitus.

Beta-blockers are the most commonly used drugs in the treatment of hypertension in pregnancy and are also frequently used in the management of conditions, such as thyrotoxicosis, hypertrophic cardiomyopathy, and mitral stenosis.[16-19] In this study, in line with the previous reports, the most commonly used CVMs during pregnancy were betablockers, diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin receptor blockers, respectively. In addition, 80% of the mothers whose pregnancies ended in miscarriage or elective termination used beta-blockers. Beta-blockers can cross the placenta and may cause potential physiological changes in the fetus.[20] Although there are inconsistent data about the relationship between the use of beta-blockers in pregnancy and the risk of fetal growth restriction, preterm birth, cardiac malformations, and perinatal mortality, there are some reports indicating that direct relationship could not be established due to methodological limitations in the interpretation of available data and presence of confounding factors. However, it is also reported that uncontrolled hypertension during pregnancy may increase the risk of maternal and fetal adverse events such as preeclampsia, premature birth, gestational diabetes, fetal growth restriction, and intrauterine demise.[21-25]

In the current study, amiodarone with concomitant medications was used in a pregnancy ended in miscarriage. Amiodarone and desethylamiodarone, its major metabolite, can cross the placenta and reach 9 to 14% of maternal serum concentrations in fetus.[25] The available data are limited to identify the fetal risk related to amiodarone use in pregnancy. Amiodarone use during pregnancy may also increase the risk of neonatal hypothyroidism with or without goiter and predisposes to neonatal hyperthyroxinemia. It may be also associated with fetal bradycardia, long QT syndrome, ventricular septal defect, prematurity, and death. Amiodarone can be used during pregnancy, if the potential benefit to the mother justifies the possible risk to the fetus. Neonatal electrocardiogram and thyroid functions monitoring are also recommended.[25]

To the best of our knowledge, previous reports are usually limited to the use of CVMs alone during pregnancy, and are lacking the information regarding pregnancy outcomes related to their use with concomitant medications. Furthermore, other confounding factors that may affect pregnancy outcomes such as maternal age, smoking or alcohol use, radiation exposure, and chronic disease should be considered. Our relatively low sample size is the main limitation of this study. Although the number of the cases in this study is limited, our results may contribute to the literature. To achieve more accurate results, further large-scale, prospective studies are needed investigating specific CVMs groups.

In conclusion, based on our study results, it is not possible to establish a definite causality relationship between pregnancy outcomes and CVMs exposure. Nevertheless, we believe that the results of this study can contribute to the existing body of knowledge in this field and provide additional information to the physicians regarding the teratogenic risks of CVMs exposures during pregnancy.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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