Potential teratogenecity risk and prescription drug use among pregnant women attending maternal and child health clinic of Kemisse General Hospital, Northeastern, Ethiopia CURRENT

Drug use during pregnancy requires special consideration because both fetus and the mother are affected. Drug teratogenicity is most likely to occur when drugs are taken during first trimester of pregnancy when fetal organs are formed. In addition, drugs at second and third trimester may affect the growth and functional development of the fetus or have toxic effect on fetal tissues. The objective of this study was to assess potential teratogenecity risk and drug use pattern in Kemisse General Hospital. An institution based cross sectional study was conducted by reviewing a one year medical records (from January 1, 2010 to December 31, 2011) of pregnant women attending maternal and child health clinic of the hospital. Systematic random sampling was employed to select a total of 263 pregnant women. Structured data abstraction format was used for collection of data and then data were coded, entered and analyzed by using Statistical Package for Social Sciences version 23. medications

drugs from category C; and the rest 7 (1.6%) drugs from category D. There was no any drug from category X.

Conclusion
Approximately one third of the pregnant women encountered with drugs from category B, C and D. However, there were no FDA category C and D drugs prescribed in first trimester.
There was no drug utilized by pregnant women from FDA pregnancy risk category X.
Background Drugs use in pregnancy should always question two important queries and maintain a fine balance of them; no harm should be posed to the baby due to the drug, and no harm must come to the mother or baby because of inadequate treatment (1). Medication use during pregnancy has been an issue of serious concern and needs monitoring since historical milestone of thalidomide disaster during the 1960s (2). The physiologic, pharmacokinetic and pharmacodynamic changes occur during pregnancy requires special therapeutic consideration in pregnant and lactating women. Not only the changes have occurred, but also these physiologic changes are not fixed throughout pregnancy but rather reflect a continuum of change as pregnancy progresses. Moreover, pregnant women have been often excluded from clinical trials and extrapolation of pharmacokinetics data from studies performed in non-pregnant adults or evidences generated from animal studies are not often suitable (3). Therefore, pregnancy management using medications has been challenging to both health care providers and pregnant women, given the fear of teratogenicity effects and the potential for fetal harms.
A large number of studies have reported that the utilization of a large number of drugs during pregnancy (4)(5)(6)(7)(8). Substantial number of drugs was also used from Food and Drug administration (FDA) pregnancy risk category D and X (9). Hence this study was carried out to evaluate the pattern of drug use and potential teratogenicity risk to fetus in women attending Maternal and Child Health (MCH) clinic of Kemisse General Hospital (KGH) in eastern Amhara, Ethiopia.

Study area, design and period
The study was conducted at Kemisse General Hospital (KGH), located in Northeast Ethiopia, Oromia Special Zone, Amhara National Regional State, 331 km away from north of Addis Ababa. The hospital is the only general hospital in the zone and currently serving about 1.2 million catchment population from all population in the zone and nearby districts. An institution based cross sectional study was conducted from March 1 to April 20, 2019 by reviewing a one year medical records (from January 1, 2010 to December 31, 2011) of pregnant women attending maternal and child health (MCH) clinic of the hospital.

Study population
All medical records of pregnant women who attended MCH clinic of KGH from Jan 1, 2010 to Dec 30, 2011 were taken as a study population. Women came for Antenatal Care (ANC) and enrolled in routine ANC program from Jan 1, 2010 -Dec 31, 2011.

Sample size determination and sampling technique
By using single population proportion formula, the sample size was determined as follows: Where, nf = final sample size, ni = initial sample size, and N= study population.
Systematic random sampling was employed to select the study units.

Data collection processes and data quality control
The data abstraction format used contained information regarding to obstetric history (age, trimesters of pregnancy, gravidity, number of visits), clinical and drug related data (common maternal disorders, common classes of drugs in each trimesters, and prescribed medications) and FDA pregnancy risk category. Pretest was done at Bati primary hospital located in the nearby town. Important corrections and data cleaning on daily basis were made.

Data processing and analysis
The data were coded, entered and analyzed by using Statistical Package for Social

Obstetric history of pregnant women
A total of 263 pregnant women medical records were reviewed for this study. first trimester 125(29.07%). From antibiotics, amoxicillin, ceftriaxone and amoxicillin/clavunilic acid were mostly prescribed whereas paracetamol and diclofenac were frequently prescribed analgesics (Table 3).

Discussion
Out of 234 pregnant women who attended MCH clinic of a hospital, the mean age of pregnant women was 26.5 (± 6.2) years and the majority of them were between 25 to 34 years which represents the normal reproductive age groups. This finding is line with a report by Legesse B et al (7). More than half of pregnant women had four to six antenatal visits and most of them were in third trimester and started their ANC visits after the 24th week of their pregnancy. This finding is not in accordance with the reports by Fanta, et al (10)and Chanie et al (8). However, considerable numbers of pregnant women were in the first and second trimester where the critical periods of organogenesis and organ development occur and drug-induced teratogenicity is assumed to reach highest.
The prevalence of drug utilization in this study was found to be 88.97%, comparable with prevalence of 85.1 % in eastern Ethiopia, Harar (11), 87.5% in northern Ethiopia (9)and 88.4% in north west Ethiopia, Bahirdar (12). But this value is lower than a study in Nekemte (96%) (13).
Most common diseases recorded were anemia and vitamin deficiency, intestinal parasite, nausea and vomiting, dyspepsia, urinary tract infections and acute febrile illness. Hence, the majority of medications prescribed were drugs used against these problems such as iron salts and folic acid, antibiotics such as amoxicillin, ceftraixone, metronidazole and amoxicillin/clavunilic acid, gastrointestinal drugs like metoclopramide, mebendazole and omeprazole. All of these drugs were either from FDA category A, B or C. The result of study was relatively higher than study reported in Nigeria (14). This may be because of difference in maternal health problems such that intestinal parasite was among commonly presented maternal disorders in this study that increase percentage of drug utilization.
The average number of drugs per pregnant women in this study was 1.84 which indicated that it was a bit out of range of standard set by WHO (1.6-1.8) (15) as compared to the reports from studies conducted at Ayder referral hospital, Mekele and Hiwot Fana specialized university hospital, Harar (2.17, 1.21) respectively (3,11).
Looking at the medications prescribed for pregnant women, supplemental drugs utilization accounted 69% of the total drugs, which is higher than a study conducted in eight rural districts of Ethiopia where only 35.4% of pregnant women used iron supplements (16) and lower than study conducted at Addis Ababa (17) and Harar city (11) which showed that more than 90% and 84.88% of the mothers were supplemented with at least one iron/folic acid supplement respectively. Much has to be done to create awareness, access and improve supplemental drugs utilization to almost every pregnant mother.
Higher numbers of drugs were prescribed in second and third trimester of pregnancy which might increases the risk of fetal toxicity. The majority of drugs were from category A (69.1%). This finding was far higher than a study conducted at Adama referral hospital (18) and Fiche primary hospital, Ethiopia (10) and a study done in Sao Paulo (19) which indicated that 13.6%, 20.83% and 20.55% drugs were from category A respectively. However, this finding was in line with a study done in Swaziland that reported 64.9% drugs were under category A. Whereas the current study was lower than studies conducted in Hiwot Fana Specialized University Hospital (84.88%) (11), in different health facilities of Southern Tigray region (87.7%) (9) and India (91.13%) (20). The present study also showed that 19.1% of drugs were from category B, which was lower than a study conducted in Jimma (18) and Adama (21) where 60.2 % and 62.4% were prescribed from category B.
Some group of drugs from category C (10.2%) and D (1.6%) were prescribed in this study.
These values were lower than a study conducted at Addis Ababa where 21.43% and 16.96% drugs were from category C and D respectively (22). There were not drugs from category C and D prescribed during first trimester, but considerable number of drugs was prescribed during the second and third trimesters. According to present study, diclofenac and ibuprofen (those from category D) were used in third trimester for pregnant women to manage pain; however, this can cause early closure and constriction of ductus arteriosus with subsequent neonatal pulmonary hypertension and transient right-sided hypertrophic cardiomyopathy (23). Other drugs such as mebendazole, metronidazole, tramadol, and artemether/lumefantrine are only recommended for use during pregnancy when benefit outweighs risk.
Looking at the prescribing indicators, the present study showed that the percentage of drugs prescribed by the generic name was found to be 95.8%, which was comparable to a study done in Fiche Hospital (10) where 94.08% of the prescriptions were generic name drugs. Percentage of encounters with injections prescribed was 8.6%, less than a standard set by WHO (15). 8.14% of the total prescribed medications were antibiotics. Among these, amoxicillin, ceftriaxone and amoxicillin/ clavunilic acid were commonly prescribed which belongs to FDA category B drugs and are safe.

Conclusion
Most of the drugs utilized were supplemental in nature. There was no drug utilized by pregnant women from FDA pregnancy risk category X. Some drugs were utilized from FDA category D (Diclofenac and ibuprofen) for pain management, despite the fact that these drugs might have risk for pregnant women like ductusarteriosus with subsequent neonatal pulmonary hypertension and transient right-sided hypertrophic cardiomyopathy. FDA category A drugs were the most frequently prescribed drugs. However, approximately one third of the pregnant women encountered with drugs from category B, C and D which are thought to cause possible fetal harm. Hence, such inappropriate prescription of drugs should not be underestimated since it affects the life of both the mother and the fetus.
Therefore, intensive assessment of pharmacotherapy given to pregnant women should be done with respect to the FDA risk category, the gestational period, and the risk-benefit balance of a drug before its prescription. Therefore, lack of awareness in respect to drug prescription and use should be improved with the proper implementation of information, education and communication.

LIMITATION OF THE STUDY
There was insufficient drug information on patients' medical records and some patient medical records didn't have diagnosis for the prescribed drugs at all. Some medical records were incomplete. Retrospective nature of the study may not address the temporal r/ship b/n the drug exposure and the pregnancy risk. Moreover, the retrospective study did not examine over-the-counter medications and herbal medicines that the pregnant women may self medicate but still might produce teratogencity.

Ethics approval and consent to participate
The research was approved by ethical review committee of College of Medicine and Health Sciences of Wollo University. Official support letter of permission was obtained and all necessary communications was made with KGH officials. Confidentiality and privacy of information get from the patient medical record was kept throughout the data collection and entire study period.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
None