Drug‐related teratogenic and pathologic causes of birth defects in a tertiary hospital in Southwestern Nigeria

Abstract Birth defects are important causes of neonatal morbidity and mortality. A good understanding of the etiology is a vital step toward developing improved treatment and preventive strategies. We conducted an audit of medical records of newborns with birth abnormalities in a tertiary hospital over a 10‐year period, using a Pro forma designed to collect information on obstetric history, antenatal history, sociodemographics of parents, and the type of birth abnormality. Of the 180 medical records reviewed, female babies were 92 (51.1%) and male babies were 86 (47.8%). The mean age of the fathers was 38.2 + 6.2, and mothers 31.8 + 4.9. Majority 115 (63.9%) of the mothers had records of acute illnesses, and 23 (12.8%) chronic illnesses during pregnancy. Unspecified febrile illness 44 (38.3%), malaria 40 (34.8%), typhoid 8 (6.9%), hypertension 13 (56.5%), pregestational diabetes 4 (17.4%), and HIV 3 (13.0%) were the commonest maternal pathologies. Most of the documented birth abnormalities were Down's syndrome 34 (15.2%); congenital hydrocephalus 32 (14.3%); acyanotic congenital heart defect 30 (13.4%); deformity of the digits 26 (11.6%); and ventricular septal defect 20 (8.9%). The prevalence of maternal pathologies calls for concern, as these may be implicated in birth defects, therefore should be further investigated in future studies.

malformations accounting for 40% of the perinatal deaths. 7 However, in Europe, a perinatal death of 2.0% in the form of stillbirths or fetal deaths and neonatal deaths (2.5%) in the first week of life are attributed to congenital anomaly. 8 In Nigeria, available data on congenital malformations are mostly from hospital-based studies. [9][10][11] Abbey et al. 9 in a descriptive retrospective cross-sectional study conducted in a Nigerian teaching hospital reported a prevalence of 20.73 cases per 1000 live births, with the frequency in unbooked maternities significantly higher than the booked. Also, Obu et al. 11 in a cross-sectional retrospective review of medical records in a tertiary hospital in south-eastern part of Nigeria reported a prevalence of 2.8%. Surgical birth defects including cleft lip/cleft palate and neural tube defects were the commonest birth defects. Similarly, Ekanem et al. 10 in a review of birth registers reported a total of 452 cases of birth malformations of 127 929 recorded births.
About 50%-60% of all congenital malformations have no specific cause, while others are associated with known causes or risk factors. 1,2 The known causes include maternal pathologies such as fever, 12 pregestational diabetes, 13 Zika virus infection, 14 syphilis and rubella infection, 1,2 amongst others. Factors such as twining, genetic abnormalities, and family history of birth defect have also been implicated in various birth malformations. 13,15 Poor maternal nutritional status such as deficiencies in iodine and folic acid are linked to major congenital malformations like neural tube defect. 16 Conversely, high intake of vitamin A and its derivatives during pregnancy may affect the normal development of an embryo or fetus. 17 Maternal prescription drug use, including anticonvulsants, anticancer agents, and certain antidepressants may increase the risk of congenital malformations. 18,19 Advanced maternal and paternal ages are known risk factors for Down's syndrome. 20,21 Consanguinity increases the prevalence of rare genetic congenital abnormalities and nearly doubles the risk for neonatal and childhood death. 1,2 The use of social drugs such as alcohol and maternal exposure to tobacco smoke are also culpable factors of congenital malformation. 22,23 Finally, over 90% of severe congenital anomalies are found in low and middle-income countries where pregnant women often lack access to adequate and quality food. 1,2 Some of the public health measures recommended by the WHO to decrease the frequency of certain birth defects include adequate dietary intake of vitamins and minerals, particularly folic acid in adolescent girls and mothers, preventing maternal exposure to harmful substances, adequate prenatal vaccination, rational prescribing in pregnancy, amongst others. 1,2 Understanding the etiology of birth abnormalities is a vital step toward developing improved treatment and preventive strategies of congenital defects. 1,2 To the best of our knowledge, no study has attempted to investigate the teratogenic and pathologic risk factors of birth malformations in a hospital-based cohort in this part of the country. Therefore, the aim of this study was to decipher the teratogenic and pathologic risk factors of birth abnormalities by exploring the medical records of newborns with birth abnormalities over a 10-year period (from 2006 to 2016) in a tertiary hospital located in southwestern Nigeria.

| MATERIALS AND METHODS
The study center, Lagos University Teaching Hospital (LUTH) is a major tertiary hospital in Southwestern Nigeria, which often serves as a referral center for patients in Lagos State and its environs. Most of the cases of birth abnormalities in this hospital were referred from other hospitals. At the Medical Records Department, eligible cases were identified from the birth defect registry; the file numbers were used to recover the case files, and the cases were thoroughly reviewed one after the other by the investigator. Relevant information such as the demographics of the babies and their parents, antenatal and obstetric histories, parents' social histories, specific diagnosis made with regard to birth abnormalities, types of birth abnormality, time birth abnormality was diagnosed, pathologic state of the parents, exposure to known teratogens during pregnancy, and pregnancy outcomes (whether live birth or stillbirth), were extracted using a well-structured Pro forma.

| Ethical approval
The ethical approval for this study was granted by the Health

| Obstetric history of the newborns
The full obstetric history of the babies is presented in Table 1

| Sociodemographics of the parents
The sociodemographics of the parents are presented in Tables

| Antenatal history
The full maternal antenatal history are presented in Table 4.
Amongst the unbooked cases, 90 (50.0%) received antenatal in reported that prenatal supplementation with iron or iron plus folic acid given daily or weekly is effective in preventing anemia and iron deficiency at term, but there was no significant association between prenatal iron and folic acid supplementation with reduction in substantive maternal and neonatal adverse clinical outcomes. 27 However, the WHO recommends daily oral iron and folic acid supplementation with 30-60 mg of elemental iron and 0.4 mg folic acid for pregnant women to prevent maternal anemia, puerperal sepsis, low birth weight, and preterm birth. 1,2 Although, in this present study, the prescribed prenatal multivitamin complied with the WHO recommendation of 0.4 mg daily folic acid in pregnancy but the iron content (17 mg) is far less than the daily requirement in pregnancy.
The impact of low iron intake during pregnancy and poor compliance to the antenatal medications may be connected with the documented birth abnormalities. In the present study, the level of maternal compliance to the prescribed prenatal multivitamins was not fully captured, but recent data from Ontario, Canada revealed that compliance is less than optimal among women using prenatal vitamins; hence 40% of women of reproductive age do not achieve therapeutic systemic levels of folate needed to prevent neural tube defects. 28 In the scientific literatures, there appears to be some conflicting information regarding the safety of multivitamin use in pregnancy.
For instance, one study reports that maternal periconceptional intake of vitamin E is associated with congenital heart defects (CHDs), 29 while another study reports that Vitamin E intake during pregnancy does not carry any risk of birth abnormalities. 30 Also, it has been reported that women with excessive serum copper concentrations have a significantly increased risk of having offspring with a CHD, whereas, a low maternal zinc status might have a correlation with CHD. 31 In a similar report, it was stated that within the normal range of maternal serum zinc and copper concentrations, there is no variation in risk of neural tube defects but women with very high serum zinc levels may have an increased risk of neural tube defects. 32 Further, a case-control study provides evidence that suggests an association between concentrations of maternal zinc and the risk of orofacial clefts in offspring. 33 Also, studies have shown that elevated placental concentrations of manganese may be associated with increased risks of neural tube defect. 34 In the present study, unspecified febrile conditions, hypertension, and pregestational diabetes, were the most documented maternal pathologies. However, a causal relationship between these pathologic conditions and the documented birth abnormalities could not be directly established because of possible effects of the medications used in managing these disease states. However, in a population-based retrospective cohort, febrile illness with no multivitamin use was associated with generally increased risk of some birth defects including orofacial, central nervous system, cardiovascular, limb, and abdominal abnormalities. 12 It is recommended that women who experienced fever of 38.9°C or higher for extended period of time in the first month of pregnancy should be considered at increased risk for neural tube defects and should be provided appropriate counseling. 15 It is on record that physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the etiology of major birth defects, including CHD and hypospadias. 35 In the same light, poorly controlled pregestational diabetes has also been implicated in the development of birth defects. 13 Our study has potential limitations. Aside from the incomplete documentations on maternal medication, this work is an audit of medical records; the documented congenital abnormalities were based on the clinician's assessments. This may be limited by the clinician's level of experience in managing birth defects. However, most of the assessments were supported by adequate laboratory and

| CONCLUSION
In conclusion, this retrospective audit of medical records of newborns with congenital abnormalities at the LUTH reports prevalence of maternal acute and chronic illnesses such as malaria, typhoid, hypertension, and gestational diabetes, suggesting that these pathologies or their drug treatment during pregnancy may be implicated in the development of birth abnormalities. We therefore recommend that the aforementioned pathologic states and their drug treatment during pregnancy be further investigated in future casecontrol studies to fully understand their involvement in the development of birth abnormalities.

ACKNOWLEDG EMENT
We thank the staff of Medical Records Department, LUTH for assisting in retrieving the case files from the birth defect registry and granting the investigators full access to the records.

DISCLOSURES
None declared.