Olof Stephansson

Research problem and specific questions: Most prescription drugs lack enough evidence on their safety for use during pregnancy. Post-marketing studies commonly focus on few selected drugs and indications, while unexpected safety signals can be missed, as may the chance to generate timely evidence on safe use. Our overall aim is to systematically gather new evidence for the safety of a comprehensive range of prescription drugs during pregnancy, using national health registers. Specific aims are to (1) implement a medication-wide association study of drug safety in pregnancy and evaluate its performance, and (2) apply statistical triangulation methods and structured qualitative review to identify relevant safety signals and evidence of safe use.Data and method: We will systematically investigate the safety of the full range of prescription drug classes (i.e., “medication-wide”) in Swedish national register data (&gt

1.5 million pregnancies 2006-2024). We will refine a hypothesis-generating statistical method (TreeScan™) suitable for hierarchical outcomes like diagnoses and that adjusts for multiple comparisons. The models will use a predefined set of important fetal/neonatal outcomes, e.g., congenital anomalies, and propensity score stratification with predefined covariables for confounding adjustment.Results from hypothesis-generating methods need replication. Therefore, found signals will be investigated also with in-depth pharmacoepidemiological models. An interdisciplinary expert panel with, e.g., pharmacoepidemiologists, obstetricians, and patient representatives, will perform a structured qualitative review to identify signals and non-signals of relevance. They will consider, e.g., statistical robustness, consistency with prior evidence, and clinical and biological plausibility.Societal relevance and utilisation: Missing drug safety evidence in pregnancy is a critical public health concern. It can cause both unsafe use and undertreatment of chronic and acute illness. This project will yield new systematic evidence on drug safety for the benefit of pregnant women and their children. It will also provide a novel active surveillance method for Swedish and international implementation.Plan for project realisation: The applicant will lead a team with a postdoctoral researcher and statistician and coordinate the work of the international expert panel. The budget includes salaries and costs for data, travels, and meetings.

Most adverse events within maternity care stem from communication and teamwork failures. Despite national and international recommendations, few interventions include person-centered care as means for safe care. The aim of this project is to evaluate the effectiveness and implementation of TeamBirth (TB)

designed to enhance teamwork and person-centered intrapartum care. TB will be evaluated at nine labor wards, covering 26% of all births in Sweden. During this four year project outcomes, processes, and implementation will be addressed in four work packages (WPs). The research group is multidisciplinary with extensive knowledge in epidemiology, implementation science, and biostatistics. WP1. Patient safety and person-centered care: Interrupted time series design using data from the Swedish Pregnancy Register & Questionnaire. WP2. Patient reported experiences: TBs contribution to person-centered care will be explored by validated questionnaires to women. WP3. Process measures: Patient safety climate and interprofessional teamwork will be investigated using a longitudinal cross-sectional design with validated scales to staff. WP4. Process evaluation: A mixed method design using data from questionnaires and interviews. Adverse events are devastating for those involved and highly costly for society, highlighting the urgent need for interventions. This project will advance the field of patient safety and contribute to new knowledge benefiting women, their infants, and society.

Research problem and specific questionsInfants are at risk of contracting severe respiratory infections such as whooping cough and infection with respiratory syncytial virus (RSV). Vaccination of pregnant women induces a vaccine-specific immune response with the formation of antibodies that pass across the placenta to the fetus, thus protecting the child from potentially life-threatening infections. We plan to investigate factors related to the uptake of pertussis and RSV vaccination in pregnancy, as well as the safety and effectiveness of the vaccines.Data and methodBy studying data from population-based national registers of all women who have given birth in Sweden since 2014 (&gt

1 million mother-child pairs) with information on socio-economics, origin, vaccinations, diagnoses, medications, congenital malformations and deaths, we will study rare but serious side effects of the vaccines, their effectiveness and factors influencing vaccination uptake among pregnant women. In order to increase knowledge and understanding of pregnant women´s reluctance and motivation for vaccination, individual interviews with vaccinated and unvaccinated pregnant women, as well as focus group discussions with healthcare professionals, who encounter these women, will be conducted.Societal relevance and utilizationVaccination during pregnancy can reduce and prevent severe illness and death in children. At the same time, we know that vaccination uptake is influenced by socio-economic, cultural and regional factors, which can lead to unequal social conditions when it comes to the burden of disease. Further, pregnant women need to know that the vaccines are safe and effective. In this project, we have a unique opportunity to use family- and population-based, as well as qualitative data to answer these questions and thus contribute to the maintenance of society´s trust in vaccinations, customize interventions to increase vaccination uptake and reduce the burden of disease in an equal way in society.Plan for project realizationThe epidemiological analyses regarding whooping cough, as well as the qualitative study will begin in 2025. Data extraction for RSV studies will be initiated in 2025 and analyses will begin in 2026. The costs for the project consist of data extraction from national registers, implementation of the qualitative study, salaries for the applicant, co-applicants, biostatistician, as well as for a doctoral student and a post-doc, who will be recruited in 2025.

Schizophrenia and related psychoses are associated with obstetric complications but whether these associations are causal is yet to be explored. This study investigates the relationship between specific complications (e.g. preterm birth, growth restriction, hypoxia), genetic predisposition, and schizophrenia risk using a comprehensive approach integrating large-scale register-based cohort studies, genetically-informed designs, individual genotypes, and detailed familial health data.This is finally possible since we are updating our register linkage, Psychiatry Sweden, to include follow-up data until 2022, thereby enhancing our power (N=25 000 individuals with schizophrenia spectrum disorders). This presents an opportunity to combine a total-population cohort study with genetically-informed designs, such as sibling- and cousin-comparison studies, and pedigree-based family psychiatric history risk scores using familial health records in up to third degree relatives, to enhance the robustness of our causal inference. Finally, we have now genotyped a sub-set of 3000 individuals with schizophrenia and 2500 controls. Integrating  individual genotype data with health registers, we will examine the joint influence of genetics and obstetric complications on schizophrenia risk using polygenic risk scores and tentatively pathway analyses.Together these studies will add to the etiological knowledge about schizophrenia but also whether maternity care could constitute a way of prevention.

An estimated 10-15% of the four million childbirths occurring in Europe annually are classified high-risk due to maternal- or fetal complications resulting in the need for close fetal and maternal monitoring. Most of these pregnancies require hospitalization until delivery, negatively impacting patient experience, quality of life, costs, and clinical workload. However, from a quaternary prevention perspective there is an ethical and safe alternative to hospital admission: remote digital pregnancy care (RDPC) e.g., digital devices monitoring vital signs such as maternal blood pressure and fetal heart rate (CTG). RDPC´s potential is hindered by knowledge gaps on implementation, reimbursement, and cost-effectiveness. Key methodologies like hybrid care pathways and a data infrastructure are lacking. The healthcare sector needs innovative system solutions to overcome these knowledge and methodology gaps and work towards large-scale application of RDPC as a quaternary prevention solution.PREGmatic examines the multi-level perspective on quaternary prevention in pregnancies complicated by (1) pre-ecla- mpsia

(2) pre-term pre-labor rupture of membranes without contractions

(3) diabetes

(4) fetal growth restriction

(5) recurrent reduced fetal movements

(6) fetal anomaly requiring daily monitoring and subsequent hospital admission

or(7) fetal death in a previous pregnancy, with the following aims:To create care new pathways incorporating innovative RDPC in which pregnant women only receive the right care in the right place e.g., more autonomy and fewer admissions. This will be done in four hospitals across three countries (Denmark, Sweden and the Netherlands).To provide AI based clinical decision support to aid clinicians on the basis of telemonitoring to prevent overmedicali- zation while continuing to provide adequate and on time prenatal care when required.To measure the effectiveness of RDPC as a quaternary prevention measure after upscaling: a comparative study of patients in an innovative telemonitoring care pathway versus a historic control group to demonstrate the effectiveness of RDPC across different contexts.The outcomes of this study will be two-fold. First, we will develop a comprehensive overview e.g., a causal map, of determinants and outcomes from a system-based and process-oriented viewpoint. Second, we will develop a multilevel framework to unlock the power of health-related data for these patients, integrating healthcare and IT to bring information to the right place.The healthcare sectors need innovative system solutions to overcome knowledge and implementation gaps and work towards equitable large-scale application of RDPC as a quaternary prevention solution. We will provide a thorough understanding of determinants and outcomes concerning RDPC for pregnant patients requiring (academic) hospitalization at the patient level, the process level and the system level. Consequently, for daily practice the implication will be the timely identification of pregnant women who can benefit from RDPC, and adjusted RDPC care pathways to meet their specific needs. Toolkits for large scale implementation and use in daily practice will be developed and contribute to the intended transformation.

The use of smokeless nicotine products (SNP) is increasing fast among young people in high-income countries, especially among women. While the adverse perinatal effects of smoking in pregnancy are well established, and the marketing and sales of smoked tobacco products thus strictly regulated, less is known about such effects of SNP. Young women’s attitudes towards, and risk perception of, SNP use in pregnancy have never been surveyed in Sweden. We therefore propose a project to fill these knowledge gaps, taking a multidisciplinary approach. The work will rest on a recent register-based cohort study, involving all pregnancies in Sweden since 1999 (N=2.4 million) with data from health data registers. We will use “snus use”, as recorded at various points of gestation in the Medical Birth Register (MBR), as our main exposure and proxy for SNP use. In addition to perinatal outcomes (e.g., gestational diabetes and preterm birth) assessed from health registers, we will explore associations between snus use and foetal growth and growth velocity identified from ultrasounds measures. We will also validate the MBR data on snus using biomarkers analysed from maternal sera. Lastly, we will conduct semi-structured interviews with young women to improve the understanding of risk perceptions. We believe that the expected research findings are important to guide the development of interventions that can mitigate any negative public health consequences of the current surge in SNP use.

Research problem and specific questionsType-2 diabetes (T2DM) and gestational diabetes (GDM) prevalence are increasing in Sweden. Effective disease management and interventions during pregnancy could improve pregnancy outcomes and long-term health of the mother and child.This project consists of two parts

one epidemiological, and the other implementation. The epidemiological part will use contemporary cohorts to understand pregnancy outcomes in women with T2DM/GDM, in relation to disease management. Specifically, we will:Investigate the modifying effect of intensified medical surveillance and treatment – glucose control and medication.Quantify whether these associations are socially (region of birth, socioeconomic position) and BMI patterned.For the implementation part, we will explore:Barriers/facilitators for providing optimal care and self-managing diabetes during pregnancy and postnatally.Whether a co-creational process - involving health care professionals and women with T2DM/GDM - can lead to improved strategies to support person-centred care, shared decision making, and self-management of T2DM/GDM during pregnancy.Data and methodsSingleton births in the Medical Birth Register from 2003-2020 (N=2,070,000) and the Pregnancy Register from 2016-2022 (N=380,000) will be linked to quality (diabetes and neonatal) and national health registers. Regression analysis will be used to estimate the association between T2DM and GDM and maternal/infant outcomes, modified by glucose levels, treatment, BMI and social factors.The implementation part uses a multiple methods approach

focus group discussions (FGD) and individual interviews with women with T2DM/GDM and health care professionals - to explore barriers/facilitators for optimal care

and participatory action research (PAR) to co-create strategies for improved self-care.Societal relevance and utilizationEven though pregnancy is a unique opportunity for interventions targeted towards lifestyle modifications, the barriers and obstacles need to be explored. This would positively influence maternal and infant health in the short-term, reducing the likelihood of diabetes in subsequent pregnancies and later life.Plan for project realisationThe project will be conducted at the Clinical Epidemiology Division (Department of Medicine, Solna, Karolinska Institutet) and Karolinska University Hospital. Project costs include salaries (PhD student, researchers, biostatistician, data manager) and acquiring register data.

Iron deficiency is common in pregnant women. If iron deficiency is severe, this can lead to anemia. However, anemia can also be caused by other problems, such as infections and diabetes. We showed that mothers who were diagnosed with anemia at &lt

30 weeks of pregnancy had a higher risk of having a child with a neurodevelopmental disorder (NDD), such as autism, attention-deficit/hyperactivity disorder (ADHD), or intellectual disability. Because both NDDs and anemia have complex causes, we do not yet understand if maternal iron deficiency is a true cause of NDDs, hindering our ability to design appropriate clinical interventions. Too much iron can be toxic, so supplementation is not universally recommended to pregnant women. We propose to collect maternal serum samples drawn in early pregnancy and neonatal dried blood spots (i.e. PKU tests) for children affected by NDDs, their unaffected siblings, and population-based controls (total n=6200) from Swedish biobanks, and to analyze these for markers of iron status (e.g. ferritin, hepcidin). Additionally, we propose to use detailed data available from two different research cohorts to evaluate potential genetic confounding and pathways that might link maternal iron status with children’s risk of NDDs. Using a variety of complementary study designs and statistical techniques, we will critically evaluate if iron deficiency in pregnant women truly represents a modifiable risk factor for NDDs in children.

Risks for adverse maternal and fetal outcomes are increasing after the estimated delivery date (> 40 completed gestational weeks), even in low-risk pregnancies. Adverse outcomes, which must be considered, are often life-threatening or impair future health. Examples are post-partum hemorrhage (PPH) or severe birth injuries for the mother and asphyxia or stillbirth for the child. Therefore, the induction of labor (IOL) after 41 full gestational weeks is mainly recommended worldwide. This led to an increase in artificial IOL, even in middle- and low-income countries. However, despite several randomized controlled trials over the past decades, it is still under discussion at which gestational age an IOL is superior to an expectant management. The aim of the present project is to investigate at which exact gestational age after the estimated delivery date (40 full weeks of gestation) an induction of labor (IOL) can reduce the risks for adverse maternal and fetal outcomes compared to an expectant management until 42 full weeks of gestation. As a novel approach, statistical means of machine learning algorithms will be applied. The study population will include healthy pregnant women with an uncomplicated, singleton pregnancy and a gestational age of at least 40 completed weeks. Eligible pregnancies will be identified from the Swedish Medical Birth Register and the Swedish Pregnancy Register between January 1, 1997 and October 31, 2021 resulting in a study population of almost two million pregnancies. Utilizing the unique Swedish personal identity number (PIN) a further linkage to other Swedish National Health Care Registers is possible. This provide the possibility to consider a wide variety of variables (“features”) into the statistical models, including granular data on medical history, medication and socioeconomic status. Three infant (neonatal death, stillbirth, Apgar-Score < 7 at 5 minutes post-delivery) and 2 maternal (operative vaginal delivery, cesarean section) outcomes will be investigated. With unsupervised methods correlations between not only known (e.g. maternal age, Body-Mass-Index), but also still uninvestigated factors (e.g. birth history of the mother) and the outcomes will be identified and quantified by applying supervised methods. Therefore, the individual clinical characteristics of pregnant women can be considered to identify the gestational age at which the benefit of an IOL outweighs its potential harms. This could provide an individualized and evidenced-based decision-making tool for the expectant mothers and maternity care providers in the future.