Neural tube defects are abnormal formations of the brain and spinal cord that can result in death of the baby in pregnancy or after childbirth, other child death, and life-long disability. Neural tube defects are one of the most common birth defects encountered in the United Kingdom. Taking a folic acid supplement of 0.4 milligrams per day (standard doses) for women in the early stages of pregnancy or among women who may become pregnant is a critical public health intervention to reduce the risk of neural tube defects. High-dose folic acid (5 milligrams per day) is recommended for women who have certain risk factors such as a history of neural tube defects or diabetes. The purpose of this study is to determine how high-dose folic acid for preventing neural tube defects has been used over time in the United Kingdom. Other objectives are to assess whether it is associated with an increased risk of breast cancer, twinning and other multiple births, and asthma and other allergic disease in the offspring, and whether it is more effective in preventing neural tube defects as compared to standard doses. The study will be conducted among women of childbearing age using general practitioner records from the Clinical Practice Research Datalink. Findings from this study will help to guide clinical practice about the optimal dose of folic acid to prescribe before and during pregnancy.
High-dose folic acid supplementation among persons at increased risk of carrying a neural tube defect affected pregnancy is an established public health measure aimed at reducing the risk of neural tube defects. However, there is limited evidence on the relative benefits and risks of high-dose folic acid use as compared to the use of standard doses. First, we will describe trends in high-dose folic acid prescribing and determine whetherrecommendations to expand the indications for high-dose folic acid affected prescribing patterns. Second, we will determine whether high-dose folic acid use is associated with an increased risk of breast cancer, and an increased risk of having a twin (or other multiple) pregnancy or having a child with asthma and other allergic disease as compared to use of standard dose folic acid. Third, we will investigate whether high-dose folic acid use is associated with a lower chance of having a pregnancy with a neural tube defect as compared with using standard doses. We will build a cohort of women from the Clinical Practice Research Datalink (CPRD) and capture pregnancies using the CPRD Pregnancy Register. We will link to the Mother-Baby link to assess child health outcomes. We will describe trends in high-dose folic acid use over time and use interrupted times series analyses to determine whether guidelines increased high-dose folic acid prescribing. We will use time-dependent Cox proportional hazards models with inverse probability of treatment weighting to estimate the crude and adjusted incidence rates of breast cancer associated with high-dose folic acid use. We will use crude and adjusted log-binomial regression models to estimate the incidence of twinning and neural tube defects associated with its use. We will further compare the incidence of childhood asthma and other allergic disease associated with its use in pregnancy using Cox proportional hazards models.
The outcomes to be measured in this study are the prescribing of high-dose and standard-dose folic acid, incident breast cancer (lung and colorectal cancer are secondary outcomes), twinning and other multiple births, a pregnancy affected by a neural tube defect, and asthma and other allergic disease in the offspring.
Azar Mehrabadi - Chief Investigator - Dalhousie University
Azar Mehrabadi - Corresponding Applicant - Dalhousie University
Farzin Khosrow-Khavar - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Collaborator - McGill University
Robert Platt - Collaborator - McGill University
YA-HUI YU - Collaborator - Georgia State University
Practice Level Index of Multiple Deprivation;CPRD Aurum Mother-Baby Link;CPRD Aurum Pregnancy Register;CPRD GOLD Mother-Baby Link;CPRD GOLD Pregnancy Register;Rural-Urban Classification