Title: Antidepressant use during pregnancy: assessing benefits to mothers and long-term neurodevelopmental risks to children using the Clinical Practice Research Datalink
Funder: Department of Health and Social Care

Abstract: Design: Observational intergenerational cohort study using the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episodes Statistics (HES) using regression methods, propensity score matching, instrumental variable analysis, negative controls, and exposure discordant sibling control design. Setting: Representative sample of UK General practice patients Target population: Pregnant women with depression or prescribed antidepressants up to 1 year before or during pregnancy Inclusion Criteria: Women for whom a pregnancy is identified in CPRD, who were registered with the same CPRD Practice for at least 1 year before pregnancy and throughout the pregnancy period, who have a history of depression or antidepressant prescriptions recorded up to 1 year before or during pregnancy. A sub-cohort will include the mother-child pairs identified using CPRD’s mother-baby link for whom follow-up data is available until the child is at least 4 years old. Health technologies being assessed: Benefits and risks of starting antidepressants vs no drug treatment for depression during pregnancy; continuing antidepressants vs stopping antidepressants during pregnancy. Outcomes (recorded in CPRD linked to HES data): Maternal: number of GP consultations, consultations and referrals for mental health problems, self harm, inpatient admission. Child: diagnosis of autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability. Power: A recent study identified 907,642 pregnancies within the CPRD of which over 421,645 were enrolled on the CPRD mother and baby link until March 2010. Based on these numbers, and assuming a pre-pregnancy and pregnancy antidepressant exposure of 8% and 3% respectively [17], and a type 1 error probability of 0.05, there will be 90% power to detect a true relative risk of 1.63 for the least powered maternal outcome of self harm (prevalence 0.2%) and 1.58 for neurodevelopmental outcomes (prevalence 0.6%) in our main analysis. See project summary attachment for detailed power calculations. Expertise in team: The team has extensive methodological and clinical expertise in all the areas relevant to this proposal. This includes clinical expertise in perinatal and neurodevelopmental psychiatry, paediatrics, obstetrics, maternal and fetal medicine, general practice, clinical pharmacology and public health. We have strong methodological and statistical expertise particularly in longitudinal and intergenerational studies, development and application of methods of causal inference and pharmacoepidemiology and extensive experience of CPRD studies. Together, we have a strong track record of collaborative work and publishing high impact research including using CPRD and other large observational studies. We have strong PPI leadership from directors of two perinatal mental health charities who have lived experience of making decisions around antidepressant use during pregnancy.

Lay abstract: Aims: Our research questions are: i) In women with depression, what are the benefits or harms of using antidepressants during pregnancy? ii) In women prescribed antidepressants before pregnancy, what are the benefits or harms associated with their continuation during pregnancy? iii) Is antidepressant use during pregnancy associated with adverse long-term developmental problems in children such as autism, and are such associations likely to be causal? Background: Depression is common in pregnant women and if left untreated, can lead to harm to mothers and their unborn babies. Over 3% pregnant women are prescribed antidepressants. Pregnant women often ask whether they should continue using these medications, and if they could have any long term effects on their babies. Unfortunately, there is very little, and inconsistent evidence to answer this question. In animals, fetuses exposed to antidepressants can have long term developmental problems. Several recent studies have found that children whose mothers took antidepressants during pregnancy were more likely to be diagnosed with autism. However, whether these associations are caused by the medication or the mother’s depression is still unclear. This is important to know to help pregnant women and clinicians make informed decisions. Design and methods used: We will carry out the most detailed study on this topic to date. We will use data from the Clinical Practice Research Datalink (CPRD), one of the world’s largest sources of primary care data. Apart from traditional methods, we will use a range of novel methods of analysis that are designed to overcome the limitations of observational studies. These methods will enable us to carefully disentangle the role of antidepressants from the underlying depression in any observed associations. Patient and public involvement (PPI): Our PPI leads have provided important input on our research plans and will be involved in all stages of this research. They have lived experience of making decisions regarding taking antidepressants during pregnancy and now lead charities (Bluebell Care and Mothers for Mothers) that support women with perinatal mental health problems and their families. We have also carried out public consultations through our health integration team for improving perinatal mental health 'IMPROVE'. These discussions have highlighted the difficulties in the decision making process and inconsistent advice given to women due to lack of strong research evidence. Our PPI leads will be a core part of our project group meetings, in which we will discuss our plans, progress, and results. They will help set up, and facilitate our Patient Advisory Group. This group will help us think about ethical issues, discuss the meaning and relevance of our findings and to help us decide how to best disseminate our findings. Dissemination: These results will be of interest to patients, clinicians, researchers and policymakers in the UK and beyond. We will publish our results in high impact peer reviewed journals in open access format and present them at relevant national and international conferences. We will work with our PPI leads to ensure the results are disseminated appropriately through news media, newsletters, blogs and social media. We are an experienced team who will ensure the findings are disseminated promptly and accurately whilst ensuring any findings we report do not cause unnecessary alarm.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;REPRODUCTIVE HEALTH AND CHILDBIRTH