Recording of Chronic Diseases and Adverse Obstetric Outcomes during Hospitalizations for a Delivery in the National Swiss Hospital Medical Statistics Dataset between 2012 and 2018: An Observational Cross-Sectional Study.

The prevalence of chronic diseases during pregnancy and adverse maternal obstetric outcomes in Switzerland has been insufficiently studied. Data sources, which reliably capture these events, are scarce. We conducted a nationwide observational cross-sectional study (2012-2018) using data from the Swiss Hospital Medical Statistics (MS) dataset. To quantify the recording of chronic diseases and adverse maternal obstetric outcomes during delivery in hospitals or birthing centers (delivery hospitalization), we identified women who delivered a singleton live-born infant. We quantified the prevalence of 23 maternal chronic diseases (ICD-10-GM) and compared results to a nationwide Danish registry study. We further quantified the prevalence of adverse maternal obstetric outcomes (ICD-10-GM/CHOP) during the delivery hospitalization and compared the results to existing literature from Western Europe. We identified 577,220 delivery hospitalizations, of which 4.99% had a record for ≥1 diagnosis of a chronic disease (versus 15.49% in Denmark). Moreover, 13 of 23 chronic diseases seemed to be substantially under-recorded (8 of those were >10-fold more frequent in the Danish study). The prevalence of three of the chronic diseases was similar in the two studies. The prevalence of adverse maternal obstetric outcomes was comparable to other European countries. Our results suggest that chronic diseases are under-recorded during delivery hospitalizations in the MS dataset, which may be due to specific coding guidelines and aspects regarding whether a disease generates billable effort for a hospital. Adverse maternal obstetric outcomes seemed to be more completely captured

A series of observational studies focusing on different real world data sources to study health aspects during pregnancy

Maternal age at delivery is increasing in high-income countries, driven by the increasing engagement of women in higher education and career building, improved medical care during pregnancy, and advances in assisted reproduction technology. Older maternal age is associated with a higher prevalence of chronic diseases during pregnancy, which often leads to drug therapy with the possibility of adverse drug events. On the other hand, if the chronic diseases are left untreated, they can increase the risk of adverse materno-fetal outcomes. Observational research plays a major role when evaluating health aspects during pregnancy and associated materno-fetal outcomes. Main data sources being used include electronic health records, administrative claims databases, registries and prospective cohorts, and survey data. This thesis aims to contribute to the general understanding of how such observational health databases can be used to study health aspects during pregnancy. The following three studies, constituting this PhD thesis, confront different research questions in different fields, based on data from different observational data sources, but have a common focus on pregnant women. A summary of the three studies is provided in the following paragraphs. Study 1 is a review article with the title: A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy (Marxer et al., 2021, Expert Opinion on Drug Safety). We critically evaluated and summarized current evidence on the risk of congenital malformations (CM) and neurodevelopmental disorders (NDD) in children of women with epilepsy after in utero exposure to different antiseizure medications (ASM). Further, we highlighted characteristics of the main data sources being used to study the safety of ASM during pregnancy and discussed their benefits and drawbacks. Accumulating evidence mainly from (post-marketing) pregnancy and epilepsy registries, prospective cohorts, and large electronic health databases has clearly shown that in utero exposure to valproate is associated with a high risk of CM (11%) and NDD (up to 30-40%) in the child, whereas lamotrigine and levetiracetam seem to be relatively safe. Evidence on the safety of other ASM is less explicit and especially limited for more recently introduced ASM. Study 2 is a retrospective descriptive study, entitled: Changes in serum creatinine during and after pregnancy in women with or without chronic kidney disease (Marxer et al., 2021, submitted). Previous studies based on data from secondary or tertiary care suggested that kidneys may not sufficiently adapt to physiological changes during pregnancy, which may accelerate progression of chronic kidney disease (CKD). Thus, we described changes in serum creatinine (SCr) levels (proxies for renal filtration) in 14’401 pregnancies of women with or without renal impairment extracted from the UK-based primary care database Clinical Practice Research Datalink (CPRD) GOLD between 2000 and 2019. Baseline estimated glomerular filtration rate (eGFR) between 75-89 ml/min/1.73 m^2 and between 60-74 ml/min/1.73 m^2 were not associated with deterioration of renal filtration during pregnancy. However, potentially prolonged postpartum hyperfiltration in those with a baseline eGFR between 60-74 ml/min/1.73 m^2 requires further investigation. For low eGFR between 15-59 ml/min/1.73 m^2, renal adaptation was present in trimester 1 and 2. Increased median SCr levels may indicate insufficient renal function in trimester 3, but results have to be interpreted cautiously due to small sample size and potentially selective measurements. Besides describing changes in SCr levels, we captured risk factors for CKD (e.g., metabolic or autoimmune diseases). Moreover, we linked the CPRD GOLD data to inpatient hospital data for validation purposes, and to enrich our data with information on materno-fetal outcomes (birth weight, gestational age, and mode of delivery). Study 3 is an observational cross-sectional study with the title: Recording of chronic diseases and adverse obstetric outcomes during hospitalizations for a delivery in the national Swiss Hospital Medical Statistics dataset between 2012 and 2018 (Marxer et al., 2022, International Journal of Environmental Research and Public Health). The prevalence of chronic diseases during pregnancy and maternal adverse obstetric outcomes in Switzerland has been insufficiently studied but is of great public health relevance. Thus, we conducted a nationwide study (2012-2018) using data from the Swiss Hospital Medical Statistics (MS) dataset evaluating completeness of recording of 23 chronic diseases and 25 maternal adverse obstetric outcomes during 577’220 hospitalizations for a delivery (98.1% of deliveries in Switzerland). Our results suggest that chronic diseases are under-recorded during delivery hospitalizations in the Swiss MS dataset. At least one diagnosis for a chronic disease was recorded during 4.99% of delivery hospitalizations, which is substantially lower compared to a nationwide Danish registry study (15.49% between 2009 and 2013), which used the same disease definition to quantify disease prevalence during pregnancy. Under-recording of chronic diseases may be due to specific coding guidelines and aspects of whether or not a disease generates billable effort to a hospital. On the other hand, comparison of our results to studies from other European (mainly Scandinavian) countries has shown that maternal adverse obstetric outcomes are more completely captured in the MS dataset. However, future studies are needed to confirm their true prevalence. In summary, the studies presented in this thesis show how valuable observational health databases are in the field of perinatal epidemiology in order to answer research questions of public health relevance. Moreover, this thesis highlights the benefits and drawbacks of different observational databases, and underlines the value of linking data from different observational databases. Finally, this thesis highlights the importance of multi-database and multi-site collaboration among researchers and the application of advanced epidemiological methods in order to accelerate the generation of new evidence on health-related aspects during pregnancy

A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy

Introduction: The majority of women with epilepsy require treatment with antiseizure medications (ASM) throughout pregnancy. However, in utero exposure to several ASM has been associated with an increased risk of congenital malformations and/or neurodevelopmental disorders (CM/NDD) in the child, but observational evidence is methodologically heterogeneous. Areas covered: We critically evaluate current evidence on the risk of CM/NDD in children of women with epilepsy after in utero exposure to different ASM. We highlight characteristics of different data sources and discuss their benefits and drawbacks. This review includes evidence published before December 2020. Expert opinion: Given the lack of randomized controlled trials, evidence on in utero safety of ASM originates from methodologically heterogeneous post-marketing observational studies based on regis tries, prospective cohorts, and large electronic health databases. It has been clearly demonstrated that valproate is associated with a high risk of CM/NDD, whereas lamotrigine and levetiracetam are relatively safe. However, evidence is less explicit for other ASM. Reported risks vary depending on the size and origin of the underlying study population, the definition of exposure and outcomes, and other aspects of the study design. Increased collaboration between data sources to increase sample size is desirable

Survival after Stevens‒Johnson Syndrome or Toxic Epidermal Necrolysis: A United Kingdom‒Based Cohort Study

We performed a retrospective observational study to evaluate mortality after Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN). In a cross-sectional study of 434 patients hospitalized with SJS/TEN in England between 1995 and 2013 (Hospital Episode Statistics Admitted Patient Care Data), 7.4% died during the index hospitalization (5.0% of patients with SJS and 23.2% with TEN). In a second analysis, we followed a validated cohort of 477 SJS/TEN patients from the UK-based Clinical Practice Research Datalink and 1908 matched comparator patients (1995-2013) over 5 years until death or until another censoring reason occurred. In total, 23 (4.8%) of SJS/TEN patients died within 90 days after the first recorded diagnosis and 36 (7.6%) died between day 91 and the end of follow-up. We observed a HR for death of 4.86 (95% CI 2.65-8.91) during the first 90 days after SJS/TEN, which attenuated to a HR of 0.80 (95% CI 0.55-1.16) between day 91 and the end of follow up. Results were not meaningfully different within sub-groups of sex, age and body mass index. In summary, 7.4% of patients hospitalized with SJS/TEN died during the index hospitalization. Long-term mortality up to five years was not increased compared to patients without SJS/TEN

Use of Prescribed Drugs to Treat Chronic Diseases during Pregnancy in Outpatient Care in Switzerland between 2014 and 2018: Descriptive Analysis of Swiss Health Care Claims Data.

Evidence on the use of drugs during pregnancy in Switzerland is lacking. We aimed to evaluate the utilisation of drugs to treat chronic diseases during pregnancy in Switzerland. We identified all pregnancies (excluding abortions) in Swiss Helsana claims data (2014-2018). In those, we identified all claims for drugs to treat a chronic disease, which typically affects women of childbearing age. Potentially teratogenic/fetotoxic drugs were evaluated during specific risk periods. Results were demographically weighted relative to the Swiss population. We identified claims for ≥1 drug of interest during 22% of 369,371 weighted pregnancies. Levothyroxine was most frequently claimed (6.6%). Antihypertensives were claimed during 5.3% (3.9% nifedipine in T3). Renin-Angiotensin-Aldosterone System (RAAS) inhibitors were dispensed to 0.3/10,000 pregnancies during trimester 2 (T2) or trimester 3 (T3). Insulin was claimed during 3.5% of pregnancies, most frequently in T3 (3.3%). Exposure to psychotropic drugs was 3.8% (mostly Selective serotonin reuptake inhibitors (SSRIs)) and to drugs for obstructive airway diseases 3.6%. Traditional immunosuppressants (excluding corticosteroids) were claimed during 0.5% (mainly azathioprine and hydroxychloroquine), biologic immunosuppressants (Tumour necrosis factor-alpha (TNF-alpha) inhibitors and interleukin inhibitors) during 0.2%, and drugs to treat multiple sclerosis during 0.09% of pregnancies. Antiretrovirals were claimed during 0.15% of pregnancies. Patterns of drug claims were in line with treatment recommendations, but relatively rare events of in utero exposure to teratogenic drugs may have had severe implications for those involved