Medicines used in pregnancy , childbirth and lactation in a teaching hospital in Lagos , Nigeria

Objective: Pharmacotherapy during pregnancy, childbirth and lactation is very challenging because only a few medicines have been specifically tested for safety and efficacy during pregnancy. This study aimed to evaluate the pattern of medicines prescribed and their risk categories during pregnancy, childbirth and lactation. Methods: We performed a retrospective audit of the case files of registered pregnant women who received antenatal care, delivered their babies, and followed up postnatally for a period of six weeks at the Obstetrics and Gynaecology Department of the Lagos State University Teaching Hospital (LASUTH), between 1st July and 31st December 2007. The demographic and obstetric data of the patients, and the medications prescribed during pregnancy, childbirth and pueperium, were extracted. Results: Altogether, 1536 (95.8%) case files were analysed. The median age of the patients was 29 (IQR: 27-32) years; their parity was between 0 and 5. Most of the patients were ≤30 years old (64.6%), nulliparous (70.3%), booked in the second trimester (54.2%), and had spontaneous vertex delivery (67.7%). ATC group B (1577; 48.6%), followed by ATC group N (448; 13.8%), were the most frequently prescribed medicines during pregnancy. Eighteen (39.1%) different types of medicines Medicines used in pregnancy, childbirth and lactation in a teaching hospital in Lagos, Nigeria Kazeem A Oshikoya1, Ireti O Akionla2, Idowu O Senbanjo3, Ibrahim A Oreagba4, Olayinka O Ogunleye1 Sri Lanka Journal of Obstetrics and Gynaecology 2012; 34: 84-98 1 Department of Pharmacology, Lagos Sate University College of Medicine, Ikeja, Lagos, Nigeria. 2 Department of Obstetrics and Gynaecology, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria. 3 Paediatrics Department, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria. 4 Department of Pharmacology, College of Medicine, University of Lagos, Idiaraba, Lagos, Nigeria. Correspondence: Adeola Oshikoya E-mail: kazeemoshikoya@ymail.com prescribed during pregnancy were in category C risk. ATC group G medicines (65.4%) were considerably prescribed in labour. Excluding haematinics, ATC group J medicines (42.2%) were often prescribed during lactation. Conclusions: There was considerable use of medicine during pregnancy, childbirth and lactation in this study. Further studies are recommended to guide prophylactic use of antibiotics after uneventful normal childbirth.


Introduction
Pharmacotherapy during pregnancy may pose a significant risk to the mother and her unborn baby 1 .The potential teratogenesis of some medicines and the physiologic changes which affect medicine disposition in pregnancy are of great concern to clinicians and other health professionals involved in the treatment of pregnant women 2,3 .Medicines are known to account for 1% of the possible external aetiological factors of congenital defects 4,5 .Correct and cautious use of medicines in pregnancy is therefore important for safe pharmacotherapy to both the mother and her unborn baby.Medicine prescribing in pregnancy and lactation would therefore require good knowledge of teratogenecity, foetal and neonatal effects that are associated with the medicines under consideration 6 .
Generally, pharmacological treatment should be avoided in pregnancy, unless absolutely necessary, because most drugs are potentially harmful to the foetus.However, treatment becomes inevitable when a woman with a chronic medical condition becomes pregnant 7 .The chronic medical conditions such as hypertension, diabetes mellitus, epilepsy, bronchial asthma and sickle cell anaemia will require ongoing or episodic treatments 8 .In addition, there are multiple medical conditions, some of which directly result from the pregnancy or are worsened by it, that may require pharmacological therapy 9 .Also, acute medical problems such as malaria, urinary tract infection, gastrointestinal disorders, migraine and upper Vol.34, No. 3, 2012   Medicines used in pregnancy, childbirth and lactation in a teaching hospital in Lagos, Nigeria respiratory tract infection can develop during pregnancy and require pharmacotherapy 7 .Failure to manage these acute and chronic medical conditions may adversely affect the health of both the mother and her unborn baby 10 .
Pregnant women are generally excluded, for ethical reasons, from randomised clinical trials in drug development 11 .This has left questions about the safety of new medications on the developing foetus unanswered, upon drug approval and marketing.Despite the unanswered safety questions, women may intentionally or inadvertently be exposed to various prescription and non-prescription medicines before and during pregnancy.Post marketing surveillance studies have revealed association between many commonly used medicines and various birth defects  . In adition to safety issue problems, there is paucity of information to guide clinicians on the best dose of a particular medicine to recommend for pregnant women since changes in the body physiology during pregnancy have the potential to require that doses be modified.Despite the numerous knowledge gaps on safety and effectiveness of medications in pregnancy, clinicians prescribe multiple medicines for pregnant women [15][16][17] and surprisingly, these women also practice polypharmacy 18 .
Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are non-prescribed or overthe-counter medicines that are often used in pregnancy 19 .The use of aspirin and other salicylates in the last trimester can affect the foetal cardiovascular system.It can also cause alterations in maternal and foetal haemostasis mechanisms, decreased birth weight, and increased perinatal mortality 20 .The use of aspirin a week before or during labour and delivery has been associated with postpartum haemorrhage 19 .Its inhibitory effect, as well as those of the NSAIDs, on prostaglandin may also prolong labour and gestation 20 .
Breast-feeding is beneficial for the health of a mother and her child 21 .However, many medicines can be transferred into breast milk causing the risk of breast-feeding to exceed its benefit to the infant, mother, or both 22,23 .Although, a study had reported that the majority of prescription and non-prescription medicines are not found in breast milk after ingestion 24 , there is limited evidence-based data regarding the actual safety of many of these medicines, this therefore calls for caution on medicine use during lactation 25 .Aspirin, magnesium salicylate, and bismuth salicylate are excreted into the breast milk and can induce Reye's syndrome 24 .
Aspirin in the breast milk may cause neonatal rashes, platelet abnormalities and bleeding 20 .Antihistamines, including clestamine and diphenhydramine, can pass into the breast milk and produce drowsiness and irritability in the breast-fed infant 24 .
Although many studies around the world have reported increased use of prescription and nonprescription medicines during pregnancy, there is little information on the extent of medicine use during labour and lactation.The two published studies in Nigeria are based on data that were collected during pregnancy and involved pregnant women from Benin City in the South-Eastern Nigeria 15,26 ; for these reasons, existing data may not be generalised to pregnant women in Nigeria.
This study aimed to assess the medicines prescribed to pregnant women during antenatal care, childbirth and lactation at a teaching hospital in Lagos, Nigeria.In addition, the study assessed the risk associated with the medicines according to the United States Food and Drug Administration (US-FDA) pregnancy risk classification 27 and the World Health Organization (WHO) risk classification during breast feeding 28 .

Methods
This retrospective descriptive study was conducted at The Lagos State University College of Medicine (LASUTH) in Nigeria and involved registered pregnant women (booked cases) who received antenatal care, delivered their babies, and followed up postnatally for a period of six weeks (pueperium period) at the Obstetrics and Gynaecology Department (Ayinke House) of LASUTH.The study involved patients who were seen over a 6 month period, between 1st July and 31st December 2007.Patients who were HIV infected, had incomplete or unavailable medical records for review, and those who were non-ambulatory on or before two weeks of parturition, were excluded from the study.
An average of 680 pregnant women per month is newly registered for antenatal and received antenatal care at the antenatal clinic of the hospital.Medicines prescribed to the patients during antenatal visits are purchased from either the hospital or community pharmacy.
Eligible cases were identified through the main obstetric register obtained from the medical record of the antenatal clinic.A trained research nurse reviewed Sri Lanka Journal of Obstetrics and Gynaecology Kazeem A Oshikoya, Ireti O Akionla, Idowu O Senbanjo, Ibrahim A Oreagba, Olayinka O Ogunleye each case file, and using a form purposely designed for the study, extracted data on age and parity of the patient, and gestational age at booking; medical or gynaecological conditions in the pregnancy; mode of delivery; birth age of the baby; and medications (excluding vaccinations) prescribed during pregnancy, childbirth and pueperium.The lead researcher (KAO) corroborated the information extracted by the research nurse by further reviewing each case file.Where there was a disagreement, the opinion of the second researcher (IOA) superseded.
For ease of data comparison, patients' age were classified as ≤30 years or >30 years, a method that was adopted from previous studies on drug utilization during pregnancy 17 .The medicines prescribed during pregnancy, child birth and pueperium are classified according to the World Health Organisation's Anatomical Therapeutic Chemical (WHO-ATC) classification system 29 .The risk associated with the medicines prescribed in pregnancy was according to the US-FDA risk classification (Category A: controlled studies in pregnant women fail to demonstrate a risk to the foetus in the first trimester with no evidence of risk in later trimesters.The possibility of harm appears remote; Category B: presumed safety based on animal studies, with no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters; Category C: Studies in women and animals are not available or studies in animals have revealed adverse effects on the foetus and there are no controlled studies in women.Drugs should be given only if the potential benefits justify the potential risk to the foetus; Category D: There is positive evidence of human foetal risk (unsafe), however in some cases such as a life-threatening illness the potential risk may be justified if there are no other alternatives, and Category X: Highly unsafe: risk of use outweighs any potential benefit.Drugs in this category are contraindicated in women who are or may become pregnant) 27 .Medicines were assigned into a risk group using Physicians' Desk Reference 30 , Pregnancy and Lactation Reference books 31,32 , and online search from the database of safefetus.com 33.
The safety, to the mother and the baby, of medicines prescribed during child birth and pueperium was according to the WHO classification system (Category 1: compatible with breastfeeding, no known or theoretical contraindications for their use, safe for the mother to take the medicine while breast-feeding; Category 2: compatible with breastfeeding but monitor infant for side-effects, theoretically, medicine could cause side-effects in the infant but have either not been observed to do so or have occasionally caused mild side-effects; Category 3: avoid if possible, however, if used, monitor infant for side effects.Medicines reported to cause side-effects in the infant but are used if the need is really essential for the mother and no safer alternative is available; Category 4: avoid if possible as it may inhibit lactation, medicine may reduce breast milk production; and Category 5: avoid completely, medicine has dangerous side-effects on the baby.They should not be given to the mothers while breastfeeding) 28 .

Ethical issues and statistical analyses
The study protocol was approved by the ethics committee of LASUTH.All data from the medical records were coded and results presented as median and inter-quartile range (IQR), mean with standard deviation (mean ± S.D), and frequency distribution with percentage.Statistical analysis of the results was performed using the Statistical Package for the Social Sciences (SPSS), version 16 .Comparisons between age of the patient (≤30 years or >30 years) and parity or gestational age at booking (first, second or third trimester), with regards to continuous data, was made using the Pearson chi-squared test at a significance level of P<0.05.The student paired t-test was used to compare the proportion of patients with medical conditions who were ≤30 years or >30 years.
Vol. 34, No. 3, 2012   Medicines used in pregnancy, childbirth and lactation in a teaching hospital in Lagos, Nigeria Contrarily, there was no significant association between the age (≤30 years or >30 years) and time of booking of the patients (P=0.382);however, more young women booked for antenatal care in the second (552; 35.9%), third (296; 19.3%) and first (144; 9.4%) trimesters than older women.

Medicines prescribed during pregnancy
All the patients had haematinics (iron, vitamin B12 and folic acid) throughout the pregnancy, except eight patients who suffered sickle cell anaemia and had only folic acid and vitamin B12.Another 56 patients who suffered nausea and vomiting were not prescribed haematinics until their condition was stable.Since haematinics were prescribed at every stage of the pregnancy, repeated prescriptions were counted as one.Excluding haematinics, women without any medical or gynaecological problem in pregnancy (963; 62.7%) encountered a range of 0-3 medicines.The majority of these patients (827; 85.9%) were prescribed no medicine.Others had calcium lactate, ascorbic acid and paracetamol, either alone or in combinations.
Five hundred and seventy three (37.3%)patients had at least one medical or gynaecological condition in pregnancy, 57 (9.9%) of these patients had 2-3 medical or gynaecological conditions.In order to avoid overestimation of the number of different medicine exposures in pregnant women with chronic medical or gynaecological conditions, multiple prescriptions for the same medicine (antihypertensives, insulin, salbutamol, and others) were counted once.Table 1 shows the various medical and gynaecological conditions observed in the patients according to their ages and medicines prescribed.The proportion of women afflicted with medical and gynaecological conditions who were ≤30 years old were significantly higher than those who were >30 years old (P=0.018).Malaria fever (128; 22.3%) afflicted the women most, followed by upper respiratory tract infection (82; 14.3%), and nausea and vomiting (56; 9.8%).Excluding haematinics, a total of 3245 medicines, comprising of 40 different types, were prescribed to all the women throughout the pregnancy (Table 2).These women encountered an average of 3 medicines (range 2-6) per clinic visit.
The medicines prescribed in pregnancy are classified in Table 2 according to the WHO Anatomical Therapeutic Chemical system of classification.ATC group B (blood and blood-forming organs) medicines were the mostly prescribed (1577; 48.6%), followed by ATC group N (nervous system-448; 13.8%) and ATC group R (respiratory system-355; 10.9%).Table 3 describes the potential risk of the medicines prescribed in pregnancy according to the US-FDA risk classification system.The majority of the medicines prescribed were in category C (18; 39.1%), followed by category B (16; 34.8%) and category A (5; 10.9%) medicines.Six (13%) medicines were however prescribed from category D. Category X medicines which are absolutely contraindicated in pregnancy were not prescribed.

Medicines prescribed during childbirth
The list of medicines prescribed during childbirth is presented in Table 4. Medicines for genitourinary system and sex hormone (ATC group G-1576; 65.4%), predominated by oxytocin, was the most frequently prescribed in the third or fourth stage of labour.Pentazocine (272; 11.3%), promethazine (240; 10.0%) and butyl scopolamine (176; 7.3%), administered alone or in combinations, were also prescribed excessively, especially in the early intrapartum phase of labour.

Medicines prescribed during lactation
A high proportion of the patients (1505; 18.9%) had haematinics (iron, vitamin B12 and folic acid or vitamin B12 and folic acid) during early lactation.Since haematinics were prescribed throughout the six weeks postnatal period, repeated prescriptions were counted once.Table 5 shows the ATC classification of the medicines prescribed during early lactation (pueperium).Excluding haematinics, anti-infective agents (ATC group J-3353; 42.2%) were the most frequently prescribed medicines, followed by nervous system medicines (ATC group N-1714; 21.6%).Further analysis showed that, after excluding haematinics, metronidazole (1424; 17.9%), ampicillin/cloxacillin (1319; 16.6%), and paracetamol (1089; 13.7%) were the most frequently prescribed medicines during early lactation.After excluding haematinics, a total of 6438 medicines; comprising of 31 different types were prescribed to the 1536 women during early lactation (Table 5).Each woman encountered an average of 6 medicines (range 2-10).

X
None -Uncertain potassium citrate mixture (7) 1 (2.2%) +cough mixture contains chorpheniramine, pseudoephedrine, and dextromethorphan or guaifenesin † †diclofenac risk increased from "C" to "D" when used in third trimester or near term †lisinopril risk increased from "C" to "D" when used in first trimester ‡sulphadoxine/pyrimethamine risk increased from "C" to "D" when used near term

Discussion
The pattern of medical and gynaecological conditions that afflicted the patients in this study during pregnancy was similar to those reported in South-Eastern Nigeria 15 and Togo 34 but varied with those reported in Nepal 16 , South Africa 35 , and Ethiopia 36 .Malaria fever, followed by upper respiratory tract infection, was the most prevalent medical condition in this study.Similar findings have been reported in South-eastern Nigeria 15 and Togo 34 , but contrasting to emesis gravidarum, heartburn, upper respiratory tract infection, and pain related problems that were reported in other developing16, 35,36 and developed 37,38 countries.Malaria in pregnancy is a major public health problem in Nigeria and other malaria endemic countries 39 .The deleterious effects of malaria in pregnancy include maternal anaemia, intrauterine growth restriction, low birth weight, and neonatal mortality 39 .Intermittent use of sulphadoxine/pyrimethamine for malaria prophylaxis in pregnancy has been recommended by the WHO 39 and national guidelines of the Federal Republic of Nigeria for malaria treatment 40 .Unfortunately, less than 10% of the patients were treated for malaria with chloroquine, sulphadoxine/pyrimethamine, or artesunate; either as a monotherapy or polytherapy, suggesting that antimalarial prophylaxis was rarely prescribed during pregnancy.
Vol. 34, No. 3, 2012   Medicines used in pregnancy, childbirth and lactation in a teaching hospital in Lagos, Nigeria The high use of pentazocine for our patients during labour is therefore consistent with the practice in the developed countries 47,48 .
Most medicines used during lactation were prescribed immediately after parturition.Antiinfective medicines (ATC group J); comprising mostly of antibiotics used as a monotherapy or polytherapy, was the most frequently prescribed in this study.This pattern of prescription was comparable to the findings in a similar Danish large study 38 .Excluding caesarean deliveries, antibiotics were prescribed routinely after uneventful normal childbirth as prophylaxis against maternal infectious morbidity and to reduce postpartum endometritis.This practice would however require a strong enough evidence to support routine use of antibiotics after uneventful normal deliveries.
The majority of medicines prescribed during lactation were compatible with breastfeeding; however, quite a number of them would require monitoring of the infants for side effects.Although the proportion of patients who were prescribed furosemide and ciprofloxacin were low, the inhibitory effect of furosemide on lactation and the potential adverse effects of ciprofloxacin on breastfed infants 28 would require the use of alternative medicines if necessary.
A major strength of our study is using the prescription data from case files of the patients.This provides a more accurate data than interview studies that are characterised by inherent recall bias and under-ascertainment 49 .By systematically auditing the case files of the women during pregnancy, childbirth and pueperium, we were able to perform a holistic evaluation of medicines used in obstetrics; an approach that was lacking in most of the previous studies.Furthermore, our study has provided adequate data on prescription analysis on this subject which is invaluable in the development of guidelines on rational medicine use during pregnancy and maternity.Given that all medicines prescribed were unlikely to be used during pregnancy and lactation, we may have overestimated medicine use in this study.This is however a limitation of this study.

Conclusion
The study shows considerable medication use during pregnancy, childbirth and lactation.The moderate exposure during pregnancy to medicines with potential harm to the foetus, and further exposure during lactation to breastfed infants, is of great concern.It is suggested that medicine use during pregnancy and lactation should be monitored regularly by analysing prescription data.Prophylactic prescription of antibiotics after uneventful normal childbirth should be guided by evidence-based studies.

Table 1 : Medical/gynaecological conditions and the medicines prescribed to pregnant women at LASUTH in 2007
* Significant difference in the proportions P=0.018 ψ This include malaria co-infection in patients with diabetes mellitus, hypertension, heart burn, and syphilis † Sulphadoxime/pyrimethamine was prescribed either alone or in combination with other antimalarial medicines † † Metronidazole was prescribed with other antibiotics ¶ Diazepam was prescribed either alone or with lorazepam ¶ ¶ Nifedipine was prescribed either alone or with other antihypertensive medicines ⎭ Diabetes mellitus occurred either alone or co-exists with hypertension and/ or malaria ‡ Vaginal candidiasis occurs either alone or in an association with pelvic inflammatory disease and urinary tract infection Sri Lanka Journal of Obstetrics and Gynaecology