Prescription Patterns and Predisposing Factors of Benzodiazepine and Z-Hypnotic Use During Pregnancy: A Nationwide Cohort Study.

PURPOSE: The use of benzodiazepines and Z-hypnotics during pregnancy has raised significant concerns in recent years. However, there are limited data that capture the prescription patterns and predisposing factors in use of these drugs, particularly among women who have been long-term users of benzodiazepines and Z-hypnotics before pregnancy. METHODS: This population-based cohort study comprised 2 930 988 pregnancies between 2004 and 2018 in Taiwan. Women who were dispensed benzodiazepines or Z-hypnotics during pregnancy were identified and further stratified into groups based on their status before pregnancy: long-term users (with a supply of more than 180 days within a year), short-term users (with a supply of less than 180 days within a year), and nonusers. Trends in the use of benzodiazepines or Z-hypnotics and concomitant use with antidepressants or opioids were assessed. Logistic regression models were utilized to identify factors associated with use of these drugs during pregnancy, and interrupted time series analyses (ITSA) were employed to evaluate utilization patterns of these drugs across different pregnancy-related periods. RESULTS: The overall prevalence of benzodiazepine and Z-hypnotic use was 3.5% during pregnancy. Among prepregnancy long-term users, an upward trend was observed. The concomitant use of antidepressants or opioids among exposed women increased threefold (from 8.6% to 23.1%) and sixfold (from 0.3% to 1.7%) from 2004 to 2018, respectively. Women with unhealthy lifestyle behaviors, such as alcohol abuse (OR 2.48; 95% CI, 2.02-3.03), drug abuse (OR 10.34; 95% CI, 8.46-12.64), and tobacco use (OR 2.19; 95% CI, 1.96-2.45), as well as those with psychiatric disorders like anxiety (OR 6.99; 95% CI, 6.77-7.22), insomnia (OR 15.99; 95% CI, 15.55-16.45), depression (OR 9.43; 95% CI, 9.07-9.80), and schizophrenia (OR 21.08; 95% CI, 18.76-23.69), and higher healthcare utilization, were more likely to use benzodiazepines or Z-hypnotics during pregnancy. ITSA revealed a sudden decrease in use of benzodiazepines and Z-hypnotics after recognition of pregnancy (level change -0.55 percentage point; 95% CI, -0.59 to -0.51). In contrast, exposures to benzodiazepines and Z-hypnotics increased significantly after delivery (level change 0.12 percentage point; 95% CI, 0.09 to 0.16). CONCLUSIONS: In this cohort study, an increased trend of benzodiazepine and Z-hypnotic use during pregnancy among prepregnancy long-term users, as well as concomitant use with antidepressants or opioids were found. The findings have highlighted the existence of various risk factors associated with the use of these drugs during pregnancy. Utilization patterns varied across different stages of pregnancy, highlighting the need for prescription guidelines and educational services for women using these drugs during pregnancy.

Extension distribution for DNA confined in a nanochannel near the Odijk regime.

DNA confinement in a nanochannel typically is understood via mapping to the confinement of an equivalent neutral polymer by hard walls. This model has proven to be effective for confinement in relatively large channels where hairpin formation is frequent. An analysis of existing experimental data for Escherichia coli DNA extension in channels smaller than the persistence length, combined with an additional dataset for λ-DNA confined in a 34 nm wide channel, reveals a breakdown in this approach as the channel size approaches the Odijk regime of strong confinement. In particular, the predicted extension distribution obtained from the asymptotic solution to the weakly correlated telegraph model for a confined wormlike chain deviates significantly from the experimental distribution obtained for DNA confinement in the 34 nm channel, and the discrepancy cannot be resolved by treating the alignment fluctuations or the effective channel size as fitting parameters. We posit that the DNA-wall electrostatic interactions, which are sensible throughout a significant fraction of the channel cross section in the Odijk regime, are the source of the disagreement between theory and experiment. Dimensional analysis of the wormlike chain propagator in channel confinement reveals the importance of a dimensionless parameter, reflecting the magnitude of the DNA-wall electrostatic interactions relative to thermal energy, which has not been considered explicitly in the prevailing theories for DNA confinement in a nanochannel.

Measuring the wall depletion length of nanoconfined DNA.

Efforts to study the polymer physics of DNA confined in nanochannels have been stymied by a lack of consensus regarding its wall depletion length. We have measured this quantity in 38 nm wide, square silicon dioxide nanochannels for five different ionic strengths between 15 mM and 75 mM. Experiments used the Bionano Genomics Irys platform for massively parallel data acquisition, attenuating the effect of the sequence-dependent persistence length and finite-length effects by using nick-labeled E. coli genomic DNA with contour length separations of at least 30 µm (88 325 base pairs) between nick pairs. Over 5 × 106 measurements of the fractional extension were obtained from 39 291 labeled DNA molecules. Analyzing the stretching via Odijk's theory for a strongly confined wormlike chain yielded a linear relationship between the depletion length and the Debye length. This simple linear fit to the experimental data exhibits the same qualitative trend as previously defined analytical models for the depletion length but now quantitatively captures the experimental data.

Sequence-Dependent Persistence Length of Long DNA.

Using a high-throughput genome-mapping approach, we obtained circa 50 million measurements of the extension of internal human DNA segments in a 41 nm×41 nm nanochannel. The underlying DNA sequences, obtained by mapping to the reference human genome, are 2.5-393 kilobase pairs long and contain percent GC contents between 32.5% and 60%. Using Odijk's theory for a channel-confined wormlike chain, these data reveal that the DNA persistence length increases by almost 20% as the percent GC content increases. The increased persistence length is rationalized by a model, containing no adjustable parameters, that treats the DNA as a statistical terpolymer with a sequence-dependent intrinsic persistence length and a sequence-independent electrostatic persistence length.

Benzodiazepine Use During Pregnancy and Risk of Miscarriage.

Importance: Benzodiazepine use during pregnancy has raised significant concerns due to the potential harmful effects of this drug class on neonates. Studies on the association between benzodiazepine use and the risk of miscarriage are limited. Objective: To quantify the risk of miscarriage associated with benzodiazepine use during pregnancy after controlling for unmeasured confounders and exposure time trends. Design, Setting, and Participants: This was a nationwide, population-based case-time-control study using Taiwan's National Birth Certificate Application database and the National Health Insurance database. Pregnancies resulting in miscarriage between 2004 and 2018 were included in the case group and were 1:1 matched with exposure time-trend control individuals using disease risk score, considering demographic characteristics and prepregnancy comorbidities. Data were analyzed from August 2022 to March 2023. Exposures: Discordant exposures to benzodiazepines during risk period (1-28 days before miscarriage) and 2 reference periods (31-58 days and 181-208 days before the last menstrual period) were compared for each pregnancy. Main Outcomes and Measures: Miscarriage was defined as any pregnancy loss occurring between the first prenatal care visit (usually 8 weeks) and the 19th completed week of pregnancy. Results: This study comprised a total of 3 067 122 pregnancies among 1 957 601 women, 136 134 of which (4.4%) resulted in miscarriage. The mean (SD) age of the study population was 30.61 (5.91) years. The use of benzodiazepines during pregnancy was associated with an increased risk of miscarriage (odds ratio [OR], 1.69; 95% CI, 1.52-1.87), and consistent findings were observed across multiple sensitivity analyses considering different time windows and accounting for misclassification. In subgroup analyses, an increased risk of miscarriage was associated with each commonly used individual benzodiazepine, ranging from case-time-control ORs of 1.39 (95% CI, 1.17-1.66) for alprazolam to 2.52 (95% CI, 1.89-3.36) for fludiazepam. Conclusions and Relevance: This nationwide case-time-control study revealed an increased risk of miscarriage associated with benzodiazepine use during pregnancy after accounting for measurable confounders, and results were unlikely to be due to unmeasured confounding. These findings underscore the necessity for health care professionals to meticulously balance the risk-benefit ratio when considering the use of benzodiazepines to treat psychiatric and sleep disorders during pregnancy.

Concomitant use of antidepressants and benzodiazepines during pregnancy and associated risk of congenital malformations: a population-based cohort study in Taiwan.

BACKGROUND: Despite the frequent co-administration of antidepressants and benzodiazepines, the association between such concomitant use during pregnancy and the risk of congenital malformations remains inadequately explored. This study aims to examine the association between concomitant use of antidepressants and benzodiazepines during the first trimester and organ-specific congenital malformations. METHODS: We conducted a population-based cohort study using Taiwan's National Birth Certificate Application database, the Maternal and Child Health database, and Taiwan's National Health Insurance database. Pregnant people aged 15-50 years with singleton births between Jan 1, 2004, and Dec 31, 2018, were included. Use of antidepressants and benzodiazepines was defined as at least one prescription during the first trimester, and concomitant use was defined as the overlapping prescription of both drugs with an overlapping prescription period. The primary outcomes were overall congenital malformations and eight organ-specific malformations, consisting of the nervous system, heart, respiratory system, oral cleft, digestive system, urinary system, genital system, and limb malformations. Logistic regression models with propensity score fine stratification weighting approach were used to control for measured confounders. Analyses controlling for confounding by indication and sibling comparison analyses were done to address unmeasured confounders. No individuals with lived experience participated in the research or writing process. FINDINGS: The cohort included 2 634 021 singleton pregnancies, and 8599 (0·3%) individuals were concomitant users of antidepressants and benzodiazepines during the first trimester (mean age at delivery was 31·8 years [SD 5·2] for pregnancies with exposure to antidepressants and benzodiazepines vs 30·7 years [SD 4·9] for pregnancies without exposure). All study participants were female, and information about ethnicity was not available. Absolute risk of overall malformations was 3·81 per 100 pregnancies with exposure, compared with 2·87 per 100 pregnancies without exposure. The propensity score-weighted odds ratios (weighted ORs) did not suggest an increased risk for overall malformations (weighted OR 1·10, 95% CI 0·94-1·28), heart defects (1·01, 0·83-1·23), or any of the other organ-specific malformations, except for digestive system malformations, for which the weighted OR remained statistically significant after adjustment (1·63, 1·06-2·51). The absence of an increased risk for overall congenital malformations associated with concomitant use of antidepressants and benzodiazepines was supported by the analyses controlling for confounding by indication and sibling-matched comparisons. INTERPRETATION: The findings of this study suggest that the concomitant use of antidepressants and benzodiazepines during the first trimester is not associated with a substantial increase in risk for most malformation subtypes. However, considering other potential adverse effects of using both medications concomitantly, a thorough assessment of the risks and benefits is crucial for clinical decision making. FUNDING: National Science and Technology Council.

Multi-Trajectories of Intrinsic Capacity Decline and Their Impact on Age-Related Outcomes: A 20-Year National Longitudinal Cohort Study.

The existence of intrinsic capacity (IC) subtypes and their distinct impacts on age-related outcomes remain unexplored. This study sought to investigate IC impairment trajectories across domains and their associations with the risk of age-related outcomes, including falls, functional limitations, reduced quality of life (QoL) and mortality at 4- and 8-year follow-ups. The study sample comprised 1,782 older adults residing in the community from the Taiwan Longitudinal Study on Ageing (TLSA). Utilizing group-based multitrajectory modeling, distinct subtypes of IC decline trajectories across various domains were identified. Cox proportional hazard models and multivariable logistic regression analyses were employed to assess the associations between the identified subtypes and age-related outcomes. We identified four subtypes of IC decline: robust with mild decline (n=902), hearing loss with cognitive decline (n=197), physio-cognitive decline (PCD) with depression (n=373), and severe IC decline (n=310). Over the 4-year study period, compared to the robust with mild decline group, hearing loss with cognitive decline group exhibited a significantly higher risk of diminished QoL (OR=2.53 [1.66-3.86], p>0.01), whereas those in the PCD with depression group experienced an elevated risk of falls (OR=1.62 [1.18-2.23], p>0.01), as well as functional limitation (OR=2.61 [1.81-3.75], p>.01). Individuals in the severe IC decline group faced a substantially increased risk of all outcomes of interest. Distinct subtypes of IC decline across different domains have varying impacts on age-related outcomes, highlighting the need for a personalized approach to promote healthy ageing at the population level, while further investigation into specific pathophysiological mechanisms is warranted as well.