Congenital heart disease (CHD) is a general term for any heart defect in new born babies. It is the most common type of birth defect, affecting 1 in 100 babies worldwide, with around 13 affected babies born each day in the UK. Untreated, more than half of them will die. Such defects occur because something has gone wrong as the baby’s heart forms in the womb. Around one-third are due to genes passed down from the parents. The remaining two-thirds may be due to other factors, such as if the mother has diabetes, or if she takes certain medicines while pregnant. Our studies in animals have found a possible new cause of CHD which is anaemia during early pregnancy. Anaemia happens when a person is low in haemoglobin, a protein that carries oxygen in the blood. The link between anaemia in pregnant women and CHD in babies may be important in humans, as anaemia is a major global problem, affecting one third of the world’s population. However, there is little research looking at this link in humans. We will use the Clinical Practice Research Datalink to look at whether the mothers of children with CHD are more likely to be anaemic than mothers of children with normal hearts. If so, we will be able to calculate by how much anaemia increases CHD risk. Our results may suggest whether women of childbearing age need to supplement their diets with iron prior to pregnancy to avoid anaemia
We aim to investigate the association between maternal anaemia during early pregnancy and congenital heart disease (CHD) in offspring. Aim 1 is to investigate the association between: (i) maternal first trimester haemoglobin levels and CHD in offspring; (ii) maternal anaemia and CHD; (iii) types of anaemia and CHD; (iv) maternal haemoglobin and CHD-specific infant mortality/stillbirth/miscarriage/pregnancy termination. Aim 2 will investigate the same objectives within the sub-population of offspring with Down Syndrome (DS). The final aim is to explore the relationships between other maternal risk factors and CHD in the offspring. Study population will be mother-baby pairs with a coded pregnancy starting 1998-2020 and maternal haemoglobin level recorded during the first 100 days of pregnancy. Mothers with a CHD will be excluded. Primary exposure is maternal anaemia in the first trimester. Primary outcome is CHD in offspring. Data sources: (i) Pregnancy Register to include the study population; (ii) Clinical Practice Research Datalink to form mother-baby pairs; (iii) Hospital Episode Statistics admissions data including maternity data to code outcome; (iv) Office for National Statistics mortality data to code outcome; (vi) patient-level indices of multiple deprivation to account for socioeconomic status. Study design: matched case-control study with cases matched to five controls by pregnancy start date (+/-6 months) and General Practice. Cases will be mother-baby pairs where child has a diagnosis of CHD in the five years after birth or CHD-specific mortality/stillbirth/miscarriage/termination. Controls will be pairs with child not diagnosed with CHD in the first five years. Conditional logistic regression analyses will be undertaken grouped on matched sets and adjusted for other potential confounders. Analyses will be repeated for continuous haemoglobin, categorical anaemia, and type of maternal anaemia. The research would benefit patients as peri-conceptional iron supplementation could be a low-cost intervention to prevent some cases of CHD, including in children with DS.
Primary Outcome: Congenital heart disease (CHD) identified in live born children, including: atrial and ventricular septal defects; atrioventricular septal defect; patent ductus arteriosus; tetralogy of Fallot; right- and left outflow tract obstruction; aortic and pulmonary valve defects; Ebstein’s anomaly; transposition of the great arteries; common arterial trunk; and aortic arch anomalies.
Secondary Outcomes: Infant mortality upto age 5 within the primary case series.
Separate case series of pregnancies that resulted in a stillbirths miscarriage and termination will also be extracted as separate case series.
Clare Bankhead - Chief Investigator - University of Oxford
Sharon Tonner - Corresponding Applicant - University of Oxford
Brian Nicholson - Collaborator - University of Oxford
Cynthia Wright Drakesmith - Collaborator - University of Oxford
Duncan Sparrow - Collaborator - University of Oxford
Manisha Nair - Collaborator - University of Oxford
Margaret Smith - Collaborator - University of Oxford
Rafael Perera - Collaborator - University of Oxford
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;CPRD Aurum Mother-Baby Link;CPRD Aurum Pregnancy Register;CPRD GOLD Mother-Baby Link;CPRD GOLD Pregnancy Register