Preventable warfarin-induced birth defects: A missed opportunity?

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0. RESEARCH Preventable warfarin-induced birth defects: A missed opportunity? M Conradie,1 MB ChB, DCH, FCMG (SA), MMed (Med Gen); B D Henderson,1 MB ChB, DCH, MMed (Paed); C van Wyk,2 MSc (Med) Gen Counselling, PhD (HPE) 1 2 Division Clinical Genetics, Department of Neurology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Division Health Sciences Education, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa Corresponding author: M Conradie () Background. Congenital abnormalities and pregnancy losses due to the teratogenic effects of warfarin are prevalent among the South African population. These are potentially preventable if the challenges and barriers faced by at-risk women are understood and addressed effectively. Objectives. To determine the practice, knowledge and attitudes regarding the teratogenic risks experienced by women administered warfarin. Methods. A descriptive study was performed. Quantitative data were collected through a researcher-administered questionnaire. The target population comprised 101 women of reproductive age who received warfarin treatment and attended a single tertiary-level anticoagulation clinic. Results. Patient-related challenges identified in this study are: language barriers, poor understanding of basic terminology and mathematics, poor contraceptive and family planning practices, lack of knowledge regarding the risks of warfarin in pregnancy and passive attitudes towards information attainment. Conclusions. Interventions are necessary to address the challenges in such settings. These include increased awareness of the teratogenic potential of specific chronic medications among healthcare providers, patients and the public. Standardised management protocols for women of reproductive age initiated on teratogenic medications should be implemented, including contraceptive and family planning discussions at follow-up visits. Improvement of the counselling skills of healthcare providers and the availability of translators or healthcare providers fluent in local languages could assist in risk reduction. S Afr Med J 2019;109(6):415-420. DOI:10.7196/SAMJ.2019.v109i6.13294 Congenital disorders or birth defects are structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth or later in life. In ~50% of all congenital anomalies, no specific cause can be identified.[1] A teratogen is any substance, agent or process that affects typical fetal development, resulting in one or more congenital disorders in the fetus. The type of teratogen, its mode of action, the embryonic process affected, the genetic predisposition, and the stage of develop ment at the time of exposure determine the type and severity of the defect. From approximately the 3rd to the 12th week of gestation – the period during which differentiation of the major organs and systems occurs – the developing embryo is most vulnerable. Known teratogens include chemical and pharmaceutical agents such as warfarin, thalidomide and alcohol; infectious agents, especially rubella, cytomegalovirus and more recently zika virus; ionising radiation; and chronic diseases such as diabetes mellitus. Other risk factors for birth defects include environmental and personal factors, such as age, general health and nutritional status of the mother, or intrauterine trauma to the developing fetus.[1,2] The US Food and Drug Administration (FDA) has a risk category classification system to indicate the level of safety of medication in pregnancy. Medication is rated from A to D according to the level of safety in pregnancy and the level of supporting evidence. For example, medication in category A is completely safe in pregnancy, while that in category D has proved to have risks in humans and should be avoided, unless the benefit for the mother is greater than the expected risk. Medication in category X is contraindicated in pregnant women or women who may become pregnant, because it is known to cause birth defects in animals and humans.[3] According to the March of Dimes global report on birth defects, 415 2006,[4] middle- and low-income countries have a higher incidence of birth defects related to teratogenic medication. This might be owing to the regulation of some of these medications being less strict and to easy over-the-counter availability. Multiple drug use is common, the awareness of the teratogenic potential of certain medications is lacking and many women are unaware of their pregnancy during the first few weeks.[4] In a South African (SA) study,[5] modelled data of genetic causes and an estimate of teratogenic causes showed that at least 1 of 15 children born (6.8%) is affected by congenital disorders or birth defects. In 19.5% of these cases, teratogens could be identified as the causative factor.[5] Warfarin, a vitamin K inhibitor, is an anticoagulant used in patients with an increased risk of thromboembolic events. Indications include prosthetic heart valve replacements, some cases of inherited or acquired thrombophilias and cardiac arrhythmias, and the treatment and prevention of recurrent venous thromboembolism (deep-venous thrombosis, pulmonary embolism).[6] In SA, there is a high burden of cardiac abnormalities among young women, mostly due to rheumatic heart disease, which requires replacement of the damaged valves with prosthetic cardiac valves and necessitates life-long anticoagulation therapy.[7,8] When used during pregnancy, warfarin crosses the placental barrier and may cause teratogenic complications, including congenital defects.[7] Therefore, it is classified as category X in the FDA risk classification system. Warfarin-induced embryopathy has a >25% risk of fetal abnormalities, especially during weeks 6 - 9 of gestation. It may also result in central nervous system abnormalities in the 2nd and 3rd trimester, possibly due to microhaemorrhages. Fetal warfarin syndrome consists of nasal hypoplasia, microphthalmia, hypoplasia of the extremities, intrauterine growth retardation, cardiac anomalies, June 2019, Vol. 109, No. 6 RESEARCH scoliosis, deafness and mental retardation.[10] Furthermore, the risk of miscarriages or stillbirths in pregnant women exposed to warfarin increases significantly.[7,9,10] Despite these risks, women with chronic conditions that necessitate anticoagulation would put their own health and life at risk by discontinuing their treatment prior to or during a pregnancy. Ideally, they need to plan pregnancies and switch to low-molecular-weight heparin (LMWH) before the 6th week of pregnancy. In pregnant women at higher risk of thromboembolism, such as those with certain mechanical valve replacements or a history of thromboembolism when receiving heparin, warfarin should be continued in the interest of the mother’s health throughout her pregnancy, w (...truncated)