Drug use in delivery hospitalization: Pelotas births cohort, 2015

ABSTRACT OBJECTIVE: Trace the pattern of drug use during delivery hospitalization. METHOD: Cross-sectional study carried out from June to October 2015, included in the 2015 Pelotas births cohort. All women living in the urban area of the city who were hospitalized for delivery were part of the sample. We collected information regarding drug prescription and drug use by mothers during the whole period of hospitalization. Sociodemographic data were obtained in interview after delivery, and other data were obtained from medical charts. The drugs were classified according to the Anatomical Therapeutic Chemical system. RESULTS: All study participants (1,392 women) used at least one drug, with the mean amount being larger the higher the age of the mother, both prepartum/during delivery and postpartum. It was also higher in cases of spinal anesthesia or general anesthesia, cesarean deliveries, school hospitals, and longer hospitalizations. Analysis of the sample as a whole showed no significant difference in the number of drugs used according to hospitalization type, but when stratified by length of hospital stay the mean was higher in SUS hospitalizations than in private and health insurance hospitalizations. Drugs for the nervous system were the most used (30.5%), followed by drugs for the alimentary tract and metabolism (13.8%). The use of anti-infective agents and drugs that act on the cardiovascular and respiratory systems was higher in mothers who underwent cesarean delivery. This study showed high drug consumption in the delivery hospitalization period, and showed cesarean delivery and epidural anesthesia as the main factors related to high drug consumption in this period. CONCLUSIONS: We found high drug consumption in the delivery hospitalization period, and the main factors were cesarean delivery and epidural anesthesia. Drugs that act on the nervous system were the most used.


INTRODUCTION
Drug use in hospitals is highly prevalent, independently of health problem or hospital sector. During delivery hospitalization, drugs are used to induce labor, reduce pain, or treat preexisting maternal diseases that require maintenance of pharmacological control. The use of these drugs, although clinically justified, may affect the health of the newborn. In all cases, the choice of drug should include evaluation of safety of use during the gestation period 1,2 .
In recent years some researches were conducted in developed countries using large databases or national administrative records, which have been increasingly used in the field of perinatal pharmacoepidemiology to attempt to address the deficiency of clinical epidemiological studies on pregnant women [3][4][5][6][7] . However, Brazil lacks pharmacoepidemiological databases to conduct studies with such objective.
The characterization of drug prescription during delivery hospitalization has been little investigated, in comparison with drug use throughout gestation 8,9 . This difference may be explained, in part, by the higher importance attributed to the teratogenic risks of drugs 8 . A study conducted in a maternity hospital of Minas Gerais analyzed all drug prescriptions during one year, but comprising prescriptions of all hospitalizations of the maternity hospital and not only those of women admitted for delivery 10 . Another study conducted in a maternity hospital of Ceará evaluated drug use in the immediate postpartum period and 15 days after hospital discharge, but not the entire delivery hospitalization period 11 .
Drug use in this period may also have undesired effects on the newborn, such as respiratory depression 9,12 . In addition, analysis of drug use between different health care services (for example, between public and private maternity hospitals) may show differences in therapeutic conducts. Investigating the improper use of certain drugs, such as the indiscriminate use of oxytocin in labor, may show irrational practices in the employment of drugs 13 .
This study aimed to characterize the pattern of drug use during delivery hospitalization.

METHODS
Cross-sectional study carried out from June 5 to October 5, 2015, included in the 2015 Pelotas births cohort (C2015). The sample comprised all women living in the urban area of the city of Pelotas, state of Rio Grande do Sul, colônia Z3 and Jardim América neighborhood of the municipality of Capão do Leão who were hospitalized for delivery in the five hospitals of the city in the study period, regardless of whether the childbirth resulted in stillborn or born alive. More details on the perinatal study of C2015 can be found in the methodological article 14 .
We collected information regarding drug prescription and drug use by mothers during the whole hospitalization period. We obtained sociodemographic data of the mothers in interview conducted shortly after childbirth, still in hospital, by previously trained interviewers of the cohort. We analyzed the following variables: age (collected in full years and categorized into the 13-19, 20-30, and 31-45 ranges), economic classification according to the criteria of the Brazilian Association of Survey Companies 15 (A, B, C, or D+E); self-reported skin color (white, black, or brown -which includes dark, brown, and indigenous), and educational level (collected in years of continuous study and categorized into the 0-4, 5-8, 9-11, or ≥ 12 ranges).
The other data were collected from medical charts, soon after hospital discharge, by previously trained Pharmacy students and nursing technicians. We registered the following information: hospital of birth, anesthesia type (spinal, epidural, topical, general, or none), delivery type (vaginal or caesarian delivery), and hospitalization type (Unified Health System -SUS, health insurance plan, or private health care). The variables for hospitalization days, hospitalization days before delivery, and hospitalization days after delivery were based on the dates of admission, delivery, and discharge.
As for the drugs used, we obtained information on the drug name, time of use (prepartum/during delivery or postpartum), and days of use. We used the International classification Anatomical Therapeutic Chemical (ATC) of the World Health Organization 16 to classify them by therapeutic groups to the fifth level, when possible. In order not to identify the hospitals, they were named with the letters from A to E, with A and C being medical school hospitals.
The information was typed directly on a tablet and later transferred to the computer, and the data were analyzed with the statistical package Stata version 12.0 (Stata Corp., College Station, USA). In the descriptive analysis, we used the analysis of variance (ANOVA) to evaluate possible associations between the mean and standard deviation (SD) of the number of drugs used in each category of exposure variables (mothers being analysis units). To analyze the distribution of the most used drugs according to therapeutic group and delivery type, anesthesia type, mother age, and birth hospital, we used the bank in the long format, considering the drug as analysis unit. For these analyses we estimated the prevalence and the 95% confidence intervals.
The project was approved by the Research Ethics Committee of the Medical School of the Federal University of Pelotas, under number 315,264, including only pregnant women who agreed to participate in the study and signed the informed consent form.

RESULTS
1,392 women participated in the study of the 4,270 who were part of the 2015 perinatal cohort study. The mean age was 27 years (SD = 6.7; minimum = 13; maximum = 45). Most of the sample (65.9%) had nine or more years of formal education and belonged to economic class C (48.7%). Only five declared being indigenous, and the same number as having yellow skin color, being grouped with those who declared having dark or brown skin (13.2%); 70.0% declared having white skin color ( Table 1). The distribution of this sample, in relation to the sociodemographic variables presented, was similar to the total of the cohort (p > 0.05). Medical school hospitals totaled more than 50% of deliveries.
The most used anesthesia was spinal anesthesia (66.7%), classification into which a woman who received epidural anesthesia was also grouped. General anesthesia was used in four mothers (0.3%) due to complications during delivery. The predominant delivery type was caesarean delivery (66.8%), as shown in Table 1. Only 2 of the 462 women who had vaginal delivery were given spinal anesthesia; 339 women were given topical anesthesia; and 118 were given none.
Analysis of the association between hospital and delivery type shows statistically significant difference, especially as to the hospital that exclusively serves the SUS and to the two hospitals that exclusively serve private health care and health insurance. The other two hospitals are mixed, serving both the SUS and private health care and health insurance. Mean hospitalization time was 3.6 days (SD=4.0), median of two days (interquartile range -IQR 25-75 2-4). After delivery, mean hospitalization time was 2.7 days (SD = 2.2), median of two days (IQR 25-75 2-4). We found no statistically significant difference in mean hospitalization days according to delivery type (3.6 days for vaginal delivery and 3.5 days for cesarean delivery), but we found statistically significant difference in the association Description of mean and standard deviation of the number of drugs used during delivery hospitalization, according to exposure variables and hospitalization time (prepartum/during delivery or postpartum), is found in Table 1. All women were given at least one drug, and the mean number was significantly higher the higher the age of the mother, both at prepartum/during delivery and postpartum. It was also significantly higher when spinal anesthesia or general anesthesia were used (in this case mainly at prepartum/during delivery), in cesarean deliveries, in medical school hospitals, and the higher the number of hospitalization days. We found no significant difference in the number of drugs used according to hospitalization type (SUS, health insurance, or private health care) when the entire sample was analyzed; however, when stratified by hospitalization period (prepartum/during delivery or postpartum), the mean number of drugs was significantly higher in SUS hospitalizations than in private health care and health insurance hospitalizations. We found no significant difference in the mean number of drugs used according to economic class (Table 1).
A total of 14,383 drugs were used. Table 2 shows the distribution of the most used drugs, classified according to the Anatomical Therapeutic Chemical system (levels 1 and 3). Drugs that act on the nervous system (ATC group N) were the most used (n = 4,274; 30.5%), followed by those that act on the alimentary tract and metabolism (ATC group A; n = 1,932; 13.8%). Table 3 shows the most used drugs that act on the nervous system, stratified by anesthesia type. For mothers given spinal anesthesia, the most frequent were bupivacaine (30.2%), morphine (23.8%), dipyrone/metamizole (18.5%), and paracetamol (12.0%). For mothers given only topical anesthesia (vaginal area), the most used drugs were paracetamol (53.5%) and bupivacaine (40.3%). The distribution of therapeutic groups according to delivery type (cesarean or vaginal delivery) is found in Table 4. Drugs that act on the nervous system, alimentary tract and metabolism, cardiovascular system and respiratory system, as well as anti-infective agents, were more used in mothers who had cesarean delivery than in those who had vaginal delivery. Greater emphasis should be given to anti-infective agents (1.6 times higher use)   and drugs that act on the cardiovascular system and respiratory system, whose prevalence rates were more than double in mothers who had caesarean delivery compared with those who had vaginal delivery. Among the drugs for the nervous system, bupivacaine was 33% more used in mothers who had cesarean delivery and morphine was used only by them, with prevalence of 8.2%. In contrast, paracetamol was two times more used in mothers who had vaginal delivery (12.5%). As for anti-infective agents, cephalotin was the most used (8.3%) and used only in women who had cesarean delivery. Metaraminol was the most used drug that acts on the cardiovascular system (5.1%), used only by women who had cesarean delivery. For vaginal deliveries, compared with cesarean deliveries, the most frequent groups were those that act on the musculoskeletal system (1.4 times higher), systemic hormonal preparations (1.7 times higher), drugs that act on the blood and blood-forming organs (2.5 times higher), and dermatological drugs (1.5 times higher), as shown in Table 4.
Ketoprofen was used only in women who had caesarean deliveries (8.6%); however, diclofenac was 2.8 times more used in women who had vaginal delivery (17.0%, compared with 4.5% for cesarean deliveries). As for systemic hormonal preparations, oxytocin is highlighted, used in 8.6% of mothers who had caesarean delivery and in 16.2% of mothers who had vaginal delivery. Ferrous sulfate was three times more used in mothers who had vaginal delivery (14.3%, compared with 3.6% for cesarean deliveries). The prevalence rates of the drugs are not presented in the table. Table 5 shows the distribution of therapeutic groups according to mother age. As for those that act on the musculoskeletal system and on the blood and blood-forming organs, the greater the age, the lower the prevalence of use, while for those that act on the cardiovascular system, the greater the age, the greater the use. Considering the musculoskeletal system, diclofenac and ketoprofen were the most used drugs; for diclofenac, the younger the mothers, the greater the use, while the opposite occurred with ketoprofen (data not presented in the table). In the therapeutic group of drugs that act on the blood and blood-forming organs, ferrous sulfate was the most used, and the younger the mothers, the greater the use. In the group of drugs that act on the cardiovascular system, metaraminol was the most used drug, but with no significant difference according to age group (data not presented in the table).

DISCUSSION
This study highlights the high drug use in mothers in the perinatal period, mainly in cesarean deliveries, and the prevalence of drugs that act on the nervous system. A cross-sectional The mean number of drugs used was higher in SUS hospitalizations, both in prepartum/during delivery and postpartum periods, inconsistently with the findings of Perini et al. 8 , which showed higher mean number of drugs in private hospitals in both periods. It is important to consider that the mean number of drugs in our study was higher in medical school hospitals, whose hospitalizations are mainly by the SUS. Drug use in these hospitals is higher probably because of the complexity of care, since they are the only ones in the city that have NICU. On the other hand, analysis of delivery type in relation to hospital type shows that the exclusively SUS medical school hospital conducts more vaginal deliveries than cesarean deliveries, while exclusively private and health insurance hospitals conduct more cesarean deliveries than vaginal deliveries. This reflects reality, because women who have health insurance or who intend to have private delivery usually schedule it to the most convenient date.
Cesarean delivery and epidural anesthesia are pointed out as the main factors associated with high consumption of drugs in the perinatal period 8,11 , which was also observed in our study, especially for drugs that act on the cardiovascular and respiratory systems, showing higher exposure to drugs and consequently higher risk to the safety of the mother and the baby. Metaraminol was only used in women who underwent caesarean delivery and, consequently, received spinal anesthesia. Metaraminol is a sympathomimetic agent used in the prophylaxis and treatment of hypotension in women who have cesarean delivery 17 .
On the other hand, women who had vaginal delivery were given more drugs that act on the blood and hematopoietic system than those who had cesarean delivery. Ferrous sulfate was the most used drug in this class, especially by younger mothers, who have a higher risk of developing anemia in gestation 18 , because they are in growth phase 19 . Dermatological drugs and those that act on the musculoskeletal system and hormonal preparations, which are generally safer in the perinatal period, due to presenting lower risk of serious adverse reactions and to being eliminated in breast milk 20,21 , were also among the most used when vaginal delivery was conducted. Thus, the drugs most used in cesarean delivery, such as bupivacaine and morphine, represent higher risk for the mother and the baby 3,22 , which points to one more harmful exposure in cesarean delivery.
A concerning fact as to the use of drugs in the perinatal period is that mothers are initiating breastfeeding, and they can interfere with milk production or cause unwanted effects on babies. Bupivacaine, medicine of the nervous system most used in this study, can interfere both beneficially and deleteriously with breastfeeding; however, there is lack of evidence, because the results are very inconsistent due to the via and form of administration, doses, time of use, etc. For example, in a randomized clinical trial conducted by Jolly et al., additional use of bupivacaine caused greater comfort during breastfeeding 23 . The use of morphine, in turn, can delay the initiation of breastfeeding and even cause child drowsiness, central nervous system depression, and even death. Even so, if the use of opiates is necessary for pain control, morphine in low doses is preferable in relation to the others 24 . Newborns seem to be particularly sensitive to the effects of narcotic analgesics, even in small doses 25 .
There are reports of episodes of cyanosis in the baby after the use of dipyrone (metamizole) by the breastfeeding mother. Dipyrone (metamizole) and its metabolites reach high concentrations in breast milk, remaining for up to 48 hours. It is recommended the use of other non-steroidal analgesic that is safer, or that the mother does not breastfeed for 48 hours after using the drug 26,27 .
Oxytocin appears as a medication widely used in this study, being widely used during childbirth. It is a hormone released during breastfeeding that seems to have tranquilizing effect on the mother 20 ; however, the administration of exogenous oxytocin to mothers with difficulty in breast-feeding showed no beneficial effect on the success of lactation or on the treatment of breast engorgement. It seems to have no effect on the child. On the other hand, several studies suggest that oxytocin administered during delivery can negatively affect breastfeeding, possibly reducing the suction behavior in the newborn [28][29][30] . A study pointed out that all rhythmic reflexes, the antigravity reflex, and the primitive neonatal reflexes were inhibited by the administration of oxytocin during delivery, an effect unrelated to dose, which could also detrimental to breastfeeding 31,32 .
Among the medicines that act on the musculoskeletal system, diclofenac was the most widely used. Despite being widely used as post-cesarean delivery analgesic, there are few data on the excretion of this drug in breast milk, with most authors considering its use acceptable during breastfeeding 33 . Diclofenac has proven effective to reduce the dose of opioids in postpartum analgesia, with no important adverse reactions, such as bleeding or uterine atonia 33 .
The longer the length of hospital stay, the greater was the number of drugs used. This leads us to think that mothers who were hospitalized more days probably had postpartum complications or are women with more co-morbidities, requiring more monitoring. On the other hand, it was observed that a significant number of women (15%) had only one day of hospitalization. According to the Brazilian Ministry of Health (MS), there is no official definition about postpartum length of hospital stay, with only one reference in Ordinance 1,016 noting that discharges should not be given before 48 hours 34 . The American Academy of Pediatrics (AAP), and the American College of Obstetrics and Gynecology (ACOG) define as early discharge that which occurs in the first 48 hours after delivery and as very early discharge that which occurs within the first 24 hours. They recommend 48 hours as mean time of hospitalization for non-complicated vaginal delivery and 96 hours for cesarean delivery 35 . This study found that 35% of mothers had early discharge and 15% had very early discharge, which puts at risk the health of both the mother and the baby. Analysis of hospitalization days in relation to hospitalization type (SUS, private health care, or health insurance) shows that women who had private or health insurance hospitalization stayed fewer days in the hospital than women who had SUS hospitalization, which reflects the following of the guidelines of the Ministry of Health by public hospitals and not by private hospitals.
A theoretical limitation of the study could be its conduct period, from June to October, very cold months in the city. However, a previous study 8 showed no seasonality in the use of medicines in the perinatal period and highlights that it enables conducting such researches in short periods of time, saving time and money. Another limitation could be that the sample was a sub-sample of the 2015 Pelotas births cohort, which could have different characteristics. However, after analysis (not shown in the results because it was performed only for comparative purposes) it was shown that the sociodemographic characteristics of the mothers participating in this study are similar to those of the other mothers of the cohort.
This study found high drug consumption in the delivery hospitalization period, and the main factors were cesarean delivery and epidural anesthesia. The most used therapeutic group was that of drugs that act on the nervous system.