A Study of Prescribing Pattern of Drugs during Pregnancy and Lactation in the Secondary and Tertiary Care Hospitals of Bangladesh: A Cross Sectional Study

Corresponding Author: Afia Ferdous Department of Pharmacy, Stamford University Bangladesh, 51 Siddeswari Road, Dhaka-1217, Bangladesh Phone: +88-01732-614841 Email: afia_sn004@yahoo.com Abstract: Using of prescribed drugs during pregnancy and lactation requires special attention because of having risk of the mothers as well as the health and life of her unborn child. Medicinal abuse usually happens due to lack of abundant information on the use of drugs during pregnancy and lactation. The main objective of this study was to assess the information about the prevalence of the use of prescribed drugs among pregnant and lactating women in Bangladesh. This was a cross-sectional study and conducted at both the Rangpur Medical College Hospital (RMCH) and Institute of Child and Mother Health (ICMH) at Dhaka in Bangladesh. Medicinal prescription copies given to 500 pregnant women and 500 lactating mothers respectively at each hospital, who attended in the hospitals, were collected. While analyzing, it was found that on an average, per prescription of pregnancy and lactation contained 2.216±0.019 (P = 0.50) and 1.199±0.014 (P = 0.05) drugs respectively. The therapeutic classes and both US-FDA pregnancy and Thomas Hale lactation categories of the drugs prescribed to pregnant women and lactating mother were also analyzed. Anti-anemic drugs including iron preparations and vitamin and mineral supplements (37.23%) were the most frequently prescribed medicines at both hospitals. Including vitamin and mineral supplements, 1098 women (49.55%) received drugs from category A; 729 women (32.90%) received drugs from category B; 309 women received drugs from category C (13.94%); 80 women (3.61%) received drugs from category D and no pregnant women received a drug from category X of the US-FDA risk classification system, whereas the highest number (605, 50.46%) of lactating mothers took drugs from L2 safe category of lactation and 355 (29.61%) lactating mothers received anti-infective drugs from therapeutic classes during visiting at both hospitals. The study shows that the prescription of harmful drugs decreases during pregnancy and lactation in Bangladesh.


Introduction
Pregnancy is a special physiological state where medication intake presents a challenge and a concern due to altered drug pharmacokinetics and drug crossing the placenta possibly causing harm to the fetus (Banhidy et al., 2005). Medication treatment in pregnancy can not be totally avoided since some pregnant women may have chronic pathological conditions that require continuous or interrupted treatment (e.g., asthma, epilepsy and hypertension) (Noha and Ahmed, 2014). Also during pregnancy new medical conditions can develop and old one can worsen (e.g., migraine, headache, hyperacidity, nausea, vomiting) requiring drug therapy (Deborah et al., 2005). However, before taking any drug (including overthe-counter drugs) or dietary supplements (including medicinal herbs), a pregnant woman should consult her health care practitioner. A health care practitioner may recommend that a woman take certain vitamins and minerals during pregnancy (Merck, 2007). Health care practitioners also consider of the benefits to the mother and the risk to the fetus while prescribing drugs during pregnancy (Rohra et al., 2008). It is not possible to avoid drugs during pregnancy, so women with certain chronic medical conditions such as epilepsy, diabetes, inflammatory bowel disease and asthma, the use of drugs is essential and benefits for mother and child may well outweigh the teratogenic risk of the drug. Other nonchronic diseases related or unrelated to the pregnancy may require medical treatment (Bakker et al., 2006).
The drugs prescribed to pregnant mothers for therapeutic purposes may cause serious structural and functional adverse effects in the developing child (Kacew, 1994). Reducing medication errors and improving patient safety are the important areas of discussion (Benjamin, 2003). It is essential to consider several factors before prescription of drugs during pregnancy. Such as, (a) Dose and duration of drug exposure is important. The larger the dose is more likely the effects. The longer the duration of drug exposure is greater chance of susceptible periods of organogenesis and developmental problem. (b) Timing of exposure is very crucial. Certain organ systems may have only limited period of susceptibility for damage. (c) Pathogenetic mechanism, teratogen produces their adverse effect by specific mechanism. (d) Host susceptibility, variability in the genetic factors related to mechanism of certain drugs. All drugs can affects the health of the mother and fetus, therefore any drugs should be administer with care during pregnancy (Pramanik and Saha, 2010).
Many mothers also require using drugs during breastfeeding. Almost all drugs transfer into breast milk and this may carry a risk to a breastfed infant. Factors such as the dose received via breast milk, pharmacokinetics and the effect of the drug in the infant need to be taken into consideration during prescribing (Sharon, 2001). Physicians also investigate the stage of the lactation, the age of the baby, the condition of the baby (particularly if preterm or ill) and the number of breastfeeds or amount of breast milk the infant receives (Denise, 2006). Most drugs likely to be prescribed to the breast feeding mother should have no effect on milk supply or on infant well-being (AAPCD, 2001). Most women who continue their drug use during pregnancy are unlikely to stop it during lactation. However, the study was conducted to appraise the patterns of drug prescriptions to pregnant women and lactating mother at secondary and tertiary care hospitals in Bangladesh.

US-FDA Pregnancy Risk Factor Categories
The USA Food and Drug Administration (FDA) classify the drugs for use in pregnancy using 5-letters system. A = adequate Controlled studies in pregnant women fail to demonstrate a risk to the fetus. Very few drugs are seen in this category. B = "Best" No risk seen in animals, but no controlled trials in pregnant women. C = "Caution" "Adverse fetal effects in animals, no controlled trials in humans." Most drugs are category C. D = "Danger" "Evidence of human fetal risk should be reserved for life-threatening disease." X = strong evidence of fetal abnormality, No therapeutic indication in pregnancy. Teratogenic Drugs: "Most Teratogenic FDA-approved medications are in categories D or X, some drugs in C" (Briggs et al., 1994).
Prescribers should look the US-FDA risk categories when prescribes to pregnancy and lactation (Rose Ann L. Jankowski, 2013).

Thomas Hale Lactation Risk Categories
Thomas Hale categorizes lactation drugs using five letters. L 1 = "Safest" Scientific studies in breastfeeding women do not show any risks to their children. L 2 = "Safe" A limited number of breastfeeding women have used this medicine and no increase in adverse effects in their children has been observed. L 3 = "Fairly Safe" Scientific studies in breastfeeding women show only minor, non-life-threatening side effects in the child. L 4 = "Possibly Risk" Scientific studies show that there is a potential risk for the child or milk production. L 5 = "Canceled" Scientific studies in breastfeeding mothers show that it is dangerous for a child if his mother is using this medicine (Hale and Rowe, 2014).

Methods
We performed a cross-sectional study at two secondary and tertiary care hospitals in Bangladesh i.e. Rangpur Medical College Hospital (RMCH) and Institute of Child and Mother Health (ICMH) in which we investigated how accurately prescriptions reflected the actual use of medications during pregnancy and lactation. Rangpur medical college is situated in Rangpur, a northern part of Bangladesh, 330 km from Dhaka and 210 km from Rajshahi. ICMH is located at Matuali in Dhaka, adjacent to Dhaka-Chittagong highway. Rangpur Medical College Hospital (RMCH) was conveniently surveyed at the first phase from 16th April 2011 to 25th June 2011 and Institute of Child and Mother Health (ICMH) was surveyed from 1 st July 2011 to 15th September 2011. The sampling units were carefully selected so as to get the data that can maximally represent the prescribing trends in Bangladesh. Ethical clearance was obtained from the Ethical Review Committee of Stamford University Bangladesh. A written clearance was obtained from the Heads of the sampling units for obtaining data from their respective Hospitals. In order to prevent bias, the prescribers were kept unaware about the collection of prescriptions. From each hospital, copies of outpatient drug prescriptions given to 500 pregnant women and 500 lactating mothers respectively were collected.
This survey consisted of multiple choice questions. An English language survey was developed based on information drawn from relevant literatures pertaining to using of prescribed drugs during pregnancy and lactation in Bangladesh. Questionnaires for patient survey covered basic questions related to their illness, their trend to stick to doctor's prescription and related information (Table 1 and 2). Questionnaires were given only to the candidates whom were requested by the representatives and among the candidates who showed spontaneous interest to respond on the questions during the survey and then the questionnaires were filled up by the representatives. Also, recommended pathological tests of pregnancy (hCG), Complete Blood Count (CBC), blood typing and antibody screening, glucose fasting plasma, CUS fasting, Glucose 2 ABF plasma, CUS 2 h ABF, Thyroid Stimulating Hormone (TSH), hepatitis B screening, rubella immunity, urine culture and sensitivity, ultrasonography and Sexual Transmitted Diseases (STDs) were recorded from the latest laboratory investigation reports (Table 3). Problems of lactating mothers those were detected by the physicians on the basis of symptoms and diagnosis, were recorded (Table  4). All the completed questionnaires, however, were pooled together. Furthermore, both the brand names and generic names of prescribed drugs were documented and then the pharmacological classes of each drug prescribed to pregnant women and lactating mother were identified by the drug index of Bangladesh.

Statistical Analysis
Statistical analysis was expressed as mean ± SEM and calculated using the software Graph Pad Quick Calcs: t test calculator, USA. All the data were analyzed using Statistical Package for Social Sciences (SPSS) software (Version 22, IBM Corporation, USA). The statistically significant difference was considered at the level of P = 0.05 and 0.50.

Results
All the pregnant women and lactating mother attending at the hospitals of two sampling units received a prescription containing at least one drug during their visits. As evident from Table 1, the maximum number of prescriptions was collected from women at both hospitals in their third trimester of pregnancy (44.0, 41.6%) followed by second (37, 35.4%) and first trimester (19, 23%), whereas breast feeding mothers who had a child of aging below 2 months received the highest number of prescriptions (74.4, 68.8%) from both RMCH and ICMH (Table 2). While analyzing the number of drugs prescribed to pregnant and lactating women, it was found out that on an average, at both centers each prescription of prescribers contained 2.216±0.019 and 1.199±0.014 drugs respectively.

Discussion
This is the first one conducted at secondary and tertiary care hospitals which demonstrates using of prescribed drugs during pregnancy and lactation in Bangladesh. Similar studies were conducted by Uchenna et al. (2007), Sharma et al. (2006) and Rohra et al. (2008). In this study, not only justified therapeutic classes of drugs but also scrutinized both US Food and Drug Administration (US-FDA) risk categories for pregnant women and Thomas Hale lactation risk categories for breastfeeding mothers to determine the precision of drugs those were prescribed by the health care providers. This study also determined the extent of prescription of drugs which are considered teratogenic for the fetus. Furthermore, both milk inducing and milk suppressing drugs were analyzed to evaluate prescription patterns in Bangladesh.
The strength of the present study is that the determination of exposure of drugs was based on physical prescriptions rather than on recall, which may lead to bias or under ascertainment (Rockenbauer et al., 2001). The average numbers of drugs prescribed per encounter in the antenatal clinics differ from the standard set by WHO (APED, 1985). The maximum numbers of drugs in a prescription during pregnancy and lactation were 6 and 5. The high numbers may have resulted from prescribing routine drugs along with other medicines. The high number may also increase the risk of adverse drug interactions (Uchenna et al., 2007).
The medicines were prescribed in brand names and this pattern is common in Bangladesh. This means that prescribers here were not complying fully with WHO recommendation that drugs should be prescribed using their international nonproprietary names. The use of brand names by physicians may relate to factors that include the influence of drug promotional activities, pressures of medical representatives who are the employees of drug-distribution or production companies, act as a source of information for both registered and unregistered physicians, offer financial inducements and many other 'gifts' during their visit to the physicians. Also, physicians may have lack of continuing education on the principles of rational prescribing and nonfamiliarity with generic names.
With regards to pathological data of pregnant women (Table 3), it was seen that Ultrasonography was the most common recommendation of physicians. The recommendation of Ultrasonography by physicians may relate to establish and confirm pregnancy date, to determine the number of fetuses, position of a fetus and examine the placental structures, to observe fetal behavior, activity and fetal growth and also to examine the fetal anatomy for presence of abnormalities. Complete Blood Count (CBC) test is another one which did more pregnant women during pregnancy. It was recommended because of developing anemia during pregnancy. During pregnancy, body produces more blood to support the growth of fetus. If body does not get enough iron or certain other nutrients, body might not be able to produce the amount of red blood cells. As a result, anemia may develop in the body. A number of mothers who visited the hospitals had been suffered of low milk supply. The most common causes of low milk supply are insufficient glandular tissue, hormonal or endocrine problems, using hormonal birth control, taking certain medications or herbs, difficult delivery and life style (Pitman, 2016).
With reference to the drugs utilized in pregnancy, it was found that anti-anemic drugs including vitamins and mineral supplements were the most commonly prescribed drugs and this result being same as that observed in Western Nepal (Das et al., 2003). Paracetamol, NSAIDs, anti-emetics, proton pump inhibitors/H2 blockers, antacids, anti-infective i.e. antibiotics and cardiovascular drugs were the other commonly used drugs. However, vitamins and mineral supplements were taken by less than 45% of women (95, 102 and 184 women in the first, second and third trimester at RMCH and 115,134 and 195 women in the first, second and third trimester at ICMH, respectively) in the present study. In a prospective survey in Southwestern Finland (Heikkila et al., 1994), iron and vitamin supplementation were the most frequently used drugs, followed by analgesics, tocolytic agents and drugs for chronic conditions and common pregnancy symptoms. In another study from Australia (Maats and Crowther, 2002), folate (69%), iron (39%) and multivitamins (27%) were the most frequently taken drugs by pregnant women.
Later on, we focused on US Food and Drug Administration (US-FDA) risk classification system to evaluate the prescribing behaviors of the physicians to pregnant women. Majority of the drugs belonged to schedule A, B and C. There are some drugs which are not completely safe but were administered as the benefits outweighed the risks. We also focused our analysis on the drugs which are documented as teratogenic in humans. The proportion of pregnant women who were prescribed potentially teratogenic drugs (1.6%) is comparable to the published results of Andrade et al. (2006), who have reported that 1.1% pregnant population in United States received a teratogenic drug. It reveals that there are certain situations where the doctors are left with no option but to prescribe teratogenic drugs when a suitable replacement is not available and/or when the benefits of the drug to the mother outweigh the possible risk to the fetus. The use of anti-epileptic drugs is a good example in this context (Eadie, 2008). However, it is an alarming trend in Bangladesh that many doctors are prescribing the drugs without knowing their significant toxic effects, drug interaction and contraindications.
It is essential that health professionals know the factors that determine the safety of the drugs used during breastfeeding. Such factors may be related to breast milk, to the mother, to the drug or to the infant (Roberto and Lamounier, 2004). Milk composition is a factor which influences how much of a drug is transferred from plasma to milk (Begg et al., 2002). Factors should also be taken into consideration that reduce the ability of mothers to metabolize or excrete the drug may increase infant exposure to the drug (Howard and Lawrence, 1999). Such cases, special precaution should be taken against prescribing drugs to nursing mothers with liver or kidney diseases due to the elevated levels and increased circulation of the drug in the mother's bloodstream. The age of the infant is another factor, should be considered when prescribes a drug used by a nursing mother. Hale classifies infants, according to their ages, as low-risk (6 to 18 months), moderate-risk (younger than 6 months) and high-risk (preterm, newborn, clinically unstable infants and those with poor renal function) for the drug of interest (Hale, 2004).
With regards to Table 7, it is seen that anti-infective drugs i.e. antibiotics were the most commonly prescribed drugs to lactating mothers and it happened because of having caesarean delivery, breast abscess and sore nipples or breasts. Out of 1000, 31.1% women underwent caesarean section to deliver their babies. As a result, more mothers received anti-infective agents to mitigate the prone of infection. Anti-ulcerants, antiemetic, dermatological and antifungal, analgesics, antipyretic, anti-inflammatory, vitamin and mineral supplements were the other commonly prescribed drugs. Furthermore, we arranged prescribed drugs following Thomas Hale Lactation Risk Categories to assess the prescribing behaviors of the health care professionals to lactating mothers. The majority of the drugs used during lactation in the present study, were from category-L 2 , followed by category-L 1 . Drugs in category-L 3 and category -L 4 were also obtained. This may have been in cases where benefits outweigh the risk. Also, we focused our analysis on the drugs which are documented as milk inducing agents and milk suppressants in breast feeding mothers. Galactogogues or milk inducing drugs may be useful in the following situations: Preterm births, maternal or infant disease, adoption or surrogate pregnancy (Gabay, 2002). Drugs which are well known for suppressing milk production, health professionals should be cautious if any of these drugs has to be actually used and should delay their introduction for as long as possible (weeks or months) (Hale, 2003). The careful indication of maternal treatment and the careful selection of drugs often allow breastfeeding to continue uninterruptedly and safely (Bagatin et al., 2001;Lamounier et al., 2000). However, the advantages of breastfeeding are enormous for the infant, whereas the risks of most medications are minimal; most of the information about drugs during lactation is based on fixed doses and on short-term studies. Breastfeeding should only be interrupted or discouraged if there is ample evidence that the drug used by the mother can be harmful to the infant, or when there is no information about the drug and the drug cannot be replaced with another one that is harmless to the infant (Roberto and Lamounier, 2004).

Conclusion
The present study reveals that the drug utilization pattern was found to be rational as almost all the drugs prescribed were compatible with both US-FDA categorization and Thomas Hale lactation categorization. Anti-anemic drugs including vitamins and minerals were prescribed to pregnant women topped the list of the prescribed medicines whilst anti-infective drugs captured top list of lactation. It is of paramount importance that pediatricians and health professionals should avoid drugs those are known as teratogenic agents and can reduce milk production.