Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries.

INTRODUCTION: Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. OBJECTIVE: To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. METHODS: This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005-2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel-Haenszel (MH) meta-analyses. RESULTS: The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98-1.34) for major congenital malformations and 1.72 (1.02-2.91) for stillbirth, which attenuated to 1.25 (0.74-2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03-1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67-1.42) for autism spectrum disorders, and 1.00 (0.78-1.29) for intellectual disability. CONCLUSIONS: Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.

Nordic Health Registry-Based Research: A Review of Health Care Systems and Key Registries.

The Nordic countries are Denmark, Finland, Iceland, Norway, and Sweden and comprise a total population of approximately 27 million. The countries provide unique opportunities for joint health registry-based research in large populations with long and complete follow-up, facilitated by shared features, such as the tax-funded and public health care systems, the similar population-based registries, and the personal identity number as unique identifier of all citizens. In this review, we provide an introduction to the health care systems, key registries, and how to navigate the practical and ethical aspects of setting up such studies. For each country, we provide an overview of population statistics and health care expenditures, and describe the operational and administrative organization of the health care system. The Nordic registries provide population-based, routine, and prospective data on individuals lives and health with virtually complete follow-up and exact censoring information. We briefly describe the total population registries, birth registries, patient registries, cancer registries, prescription registries, and causes of death registries with a focus on period of coverage, selected key variables, and potential limitations. Lastly, we discuss some practical and legal perspectives. The potential of joint research is not fully exploited, mainly due to legal and practical difficulties in, for example, cross-border sharing of data. Future tasks include clear and transparent legal pathways and a framework by which practical aspects are facilitated.

Initiation of anti-osteoporotic drugs in high-risk female patients starting glucocorticoid treatment: a population study in Norway.

Glucocorticoid use is a risk factor for osteoporosis and fractures. We studied whether women initiating glucocorticoid treatment also started anti-osteoporotic treatment, according to clinical guidelines. Women with versus without previous fracture were twice as likely to start anti-osteoporotic treatment within 1 year after initiating glucocorticoid treatment, but the cumulative incidences were low 9.1% vs. 4.6%, respectively. PURPOSE: Use of glucocorticoids (GC) is a risk factor for osteoporosis and fractures, and clinical guidelines suggest that preventive treatment with anti-osteoporotic drugs (AOD) should be considered when starting GC. Women with high risk of osteoporosis comprise those with previous fractures or a known inflammatory rheumatic disease, for whom the indication of AOD is even stronger. The purpose of these analyses was to investigate whether women initiating GC treatment also started AOD, especially those with high risk of osteoporosis. METHODS: We used data from the Norwegian Prescription Database to identify all women 55 years and older initiating GC treatment in Norway during 2010-2016 and to obtain information on use of AOD. Data from the Norwegian Patient Registry were used to obtain information on previous fractures and diagnoses. RESULTS: Among 105,477 women initiating GC treatment during 2010-2016, 3256 had started AOD and 79,638 had discontinued GC treatment after 1-year follow-up. Cumulative incidence of starting AOD after 1 year was 9.1% (95% CI: 7.9, 10.4) for women with vs. 4.6% (95% CI: 4.4%, 4.8%) for women without a previous fracture. Women with rheumatoid arthritis or another inflammatory rheumatic disease were more likely to start AOD than women with other indications. For the whole cohort, the probability of starting AOD treatment within 1 year after initiating GC increased on average 3% per year (HR = 1.03, CI: 1.01, 1.05) from 2010 to 2016. CONCLUSIONS: Having had a previous fracture or an inflammatory rheumatic disease increased the probability of treatment with AOD. However, the proportions starting AOD were much lower than clinically indicated.

The Role of Comorbidity in Mortality After Hip Fracture: A Nationwide Norwegian Study of 38,126 Women With Hip Fracture Matched to a General-Population Comparison Cohort.

Hip fracture patients often have comorbid conditions. We investigated whether the combination of comorbidity and hip fracture could explain the previously observed excess mortality among hip fracture patients as compared with the general population. Using a population-based matched study design with 38,126 Norwegian women who suffered a hip fracture during the period 2009-2015 and the same number of women in a matched comparison cohort, we matched participants on prefracture comorbidity, age, and education. We estimated relative survival and additive and multiplicative comorbidity-hip fracture interactions. An additive comorbidity-hip fracture interaction of 4 or 9 additional deaths per 100 patients, depending on Charlson Comorbidity Index (CCI) score, was observed 1 year after hip fracture. Among women with a CCI score of ≥3, 15 additional deaths per 100 patients were observed; of these, 9 deaths could be attributed to the interaction and 6 to the hip fracture per se. On the relative scale, we observed increasing heterogeneity in survival by comorbidity over time; survival was reduced by 39% after 6 years among patients with a CCI score of ≥3, while among women with no comorbidity, survival was reduced by 17% (hip fracture vs. no hip fracture). In summary, prefracture comorbidity was associated with short-term absolute excess mortality and long-term relative excess mortality.

Thirty-five-year Trends in First-time Hospitalization for Hip Fracture, 1-year Mortality, and the Prognostic Impact of Comorbidity: A Danish Nationwide Cohort Study, 1980-2014.

BACKGROUND: We examined trends in hip fracture incidence in Denmark from 1980 to 2014, trends in subsequent 1-year mortality, and the prognostic impact of sex, age, and comorbidity. METHODS: This nationwide cohort study prospectively collected data from population-based Danish registries. We included 262,437 patients with incident hip fracture and assessed comorbidity using the Charlson Comorbidity Index (CCI). RESULTS: Despite slight increases in incidence rates (IRs) of hip fracture up to the mid-1990s, the annual IR decreased by 29% from 1980 to 2014 in women but remained stable in men. Decrease affected all age groups. IR decreased in patients without comorbidity but increased with increasing comorbidity (13% in patients with moderate and 510% in patients with very severe comorbidity). Adjusted mortality rate ratios (MRRs) following hip fracture in 2010-2014 compared with 1980-1984 were 0.68 (95% confidence interval [CI] = 0.65, 0.71) within 30 days and 0.63 (95% CI = 0.61, 0.66) within 31-365 days. The mortality decreased up to 40% irrespective of comorbidity. Compared with patients with no comorbidity, those with very severe comorbidity had adjusted MRRs of 2.48 (95% CI = 2.39, 2.56) and 2.81 (95% CI = 2.74, 2.88) within 30 days and 31-365 days post-hip fracture, respectively. CONCLUSIONS: Although the incidence rate of hip fracture increased substantially with increasing comorbidity, the following 1-year mortality decreased by 40% from 1980 through 2014 irrespective of sex, age, and comorbidity level, suggesting improvement in both treatment and rehabilitation of patients with hip fracture. Comorbidity burden was, however, a strong prognostic factor for 1-year mortality after hip fracture.

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts.

Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.

Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data.

Familial correlations in birth weight and gestational age have been explained by fetal and maternal genetic factors, mainly in studies on offspring of twins. The aim of the present intergenerational study was to estimate and compare fetal and maternal genetic effects and shared sibling environmental effects on birth weight and gestational age and also on crown-heel length and head circumference. The authors used path analysis and maximum likelihood principles to estimate these effects and, at the same time, to adjust for covariates. Parent-offspring data were obtained from the Medical Birth Registry of Norway from 1967 to 2004. For the analysis of birth weight and crown-heel length, 101,748 families were included; for gestational age, 91,617 families; and for head circumference, 77,044 families. Assuming no cultural transmission and random mating, the authors found that fetal genetic factors explained 31% of the normal variation in birth weight and birth length, 27% of the variation in head circumference, and 11% of the variation in gestational age. Maternal genetic factors explained 22% of the variation in birth weight, 19% of the variation in birth length and head circumference, and 14% of the variation in gestational age. Relative to the proportion of explained variation, fetal genes were most important for birth length and head circumference.