Adverse Events After XBB.1.5-Containing COVID-19 mRNA Vaccines.

This study examines the association between XBB.1.5-containing vaccines administered as a fifth COVID-19 vaccine dose and the risk of 28 adverse events.

COVID-19 Vaccine Effectiveness Among Adolescents.

BACKGROUND: For adolescents, data on the long-term effectiveness of the BNT162b2 and mRNA-1273 vaccines against severe COVID-19 outcomes are scarce. Additionally, only a few studies have evaluated vaccine effectiveness (VE) for mRNA-1273 or heterologous mRNA vaccine schedules (ie, mixing BNT162b2 and mRNA-1273). METHODS: Nationwide register-based 1-to-1 matched cohort analyses were conducted in Denmark, Finland, Norway, and Sweden between May 28, 2021, and April 30, 2023, to estimate VE for primary COVID-19 vaccine (2-dose) schedules among adolescents aged 12 to 17 years. Cumulative incidences of COVID-19-related hospitalization (primary outcome) and laboratory-confirmed SARS-CoV-2 infection (secondary outcome) were compared for vaccinated and unvaccinated at 6 months of follow-up using the Kaplan-Meier estimator. Country-specific VE (1-risk ratio) and risk differences (RD) were combined by random-effects meta-analyses. RESULTS: The study included 526 966 primary schedule vaccinated adolescents. VE against COVID-19-related hospitalization was 72.6% (95% confidence interval [CI], 62.5-82.7) and RD was -2.8 (95% CI, -4.5 to -1.0) per 10 000 vaccinated for BNT162b2 at 6 months of follow-up compared with unvaccinated. The corresponding VE and RD were 86.0% (95% CI, 56.8-100.0) and -2.1 (95% CI, -4.0 to -0.2) per 10 000 vaccinated for mRNA-1273 and 80.7% (95% CI, 58.0-100.0) and -5.5 (95% CI, -15.5 to 4.6) per 10 000 vaccinated for heterologous mRNA vaccine schedules. Estimates were comparable when restricting to a period of omicron predominance and extending follow-up to 12 months. CONCLUSIONS: Across 4 Nordic countries, severe COVID-19 in adolescents was a rare event. Compared with unvaccinated, BNT162b2, mRNA-1273, and heterologous mRNA vaccination schedules provided high protection against COVID-19-related hospitalization, including hospitalizations during the omicron period.

SARS-CoV-2 Infection and Postacute Risk of Non-Coronavirus Disease 2019 Infectious Disease Hospitalizations: A Nationwide Cohort Study of Danish Adults Aged ≥50 Years.

BACKGROUND: Reports suggest that the potential long-lasting health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may involve persistent dysregulation of some immune populations, but the potential clinical implications are unknown. We investigated the associated risk of hospitalization due to non-coronavirus disease 2019 (COVID-19) infectious diseases following the postacute phase of SARS-CoV-2 infection. METHODS: By cross-linking data from the comprehensive Danish test and surveillance system for COVID-19 together with nationwide healthcare and demographic registers, we established a study cohort of 2 430 694 individuals aged ≥50 years, from 1 January 2021 to 10 December 2022, with no evidence of SARS-CoV-2 infection prior to study entry. Using Poisson regression, we compared the outcome rates of non-COVID-19 infectious disease hospitalizations following the acute phase of (a first) SARS-CoV-2 infection (defined as ≥29 days since the day of infection) in recovered individuals with rates among SARS-CoV-2-uninfected individuals. RESULTS: Among 2 430 694 included individuals (mean age, 66.8 [standard deviation, 11.3] years), 930 071 acquired SARS-CoV-2 infection during follow-up totaling 4 519 913 person-years. The postacute phase of SARS-CoV-2 infection was associated with an incidence rate ratio (IRR) of 0.90 (95% confidence interval [CI]: .88-.92) for any infectious disease hospitalization. Findings (IRR [95% CI]) were similar for upper respiratory tract (1.08 [.97-1.20]), lower respiratory tract (0.90 [.87-.93]), influenza (1.04 [.94-1.15]), gastrointestinal (1.28 [.78-2.09]), skin (0.98 [.93-1.03]), urinary tract (1.01 [.96-1.08]), certain invasive bacterial (0.96 [.91-1.01]), and other (0.96 [.92-1.00]) infectious disease hospitalizations and in subgroups. CONCLUSIONS: Our study does not support an increased susceptibility to non-COVID-19 infectious disease hospitalization following SARS-CoV-2 infection.

Cumulative Incidence of Thiazide-Induced Hyponatremia : A Population-Based Cohort Study.

BACKGROUND: According to drug labels, the frequency of thiazide-induced hyponatremia is unknown or uncommon to very rare (that is, <1 in 10 000 to <1 in 100), but the exact burden remains unclear. OBJECTIVE: To estimate the increase in the cumulative incidence of hyponatremia using thiazide diuretics compared with nonthiazide antihypertensive drugs in routine clinical practice. DESIGN: Population and register-based cohort study using target trial emulation. SETTING: Denmark, 1 January 2014 to 31 October 2018. PARTICIPANTS: Two target trials were emulated among persons aged 40 years or older who had no recent prescription for any antihypertensive drug, had no previous hyponatremia, and were eligible for the studied antihypertensive treatments. The first target trial emulation compared new use of bendroflumethiazide (BFZ) versus a calcium-channel blocker (CCB). The second target trial emulation compared new use of hydrochlorothiazide plus a renin-angiotensin system inhibitor (HCTZ-RASi; that is, combination pill) versus a RASi alone. MEASUREMENTS: Two-year cumulative incidences of sodium levels less than 130 mmol/L using stabilized inverse probability of treatment-weighted survival curves. RESULTS: The study compared 37 786 new users of BFZ with 44 963 of a CCB and 11 943 new users of HCTZ-RASi with 85 784 of a RASi. The 2-year cumulative incidences of hyponatremia were 3.83% for BFZ and 3.51% for HCTZ-RASi. The risk differences were 1.35% (95% CI, 1.04% to 1.66%) between BFZ and CCB and 1.38% (CI, 1.01% to 1.75%) between HCTZ-RASi and RASi; risk differences were higher with older age and higher comorbidity burden. The respective hazard ratios were 3.56 (CI, 2.76 to 4.60) and 4.25 (CI, 3.23 to 5.59) during the first 30 days since treatment initiation and 1.26 (CI, 1.09 to 1.46) and 1.29 (CI, 1.05 to 1.58) after 1 year. LIMITATION: The study assumed that filled prescriptions equaled drug use, and residual confounding is likely. CONCLUSION: Treatment initiation with thiazide diuretics suggests a more substantial excess risk for hyponatremia, particularly during the first months of treatment, than indicated by drug labeling. PRIMARY FUNDING SOURCE: Independent Research Fund Denmark.

LDL-C Reduction With Lipid-Lowering Therapy for Primary Prevention of Major Vascular Events Among Older Individuals.

BACKGROUND: Reducing low-density lipoprotein (LDL) cholesterol with lipid-lowering therapy has consistently been shown to lower the risk of cardiovascular disease in primary prevention trials where the majority of individuals are aged <70 years. For older individuals, however, evidence is less clear. OBJECTIVES: In this study, the authors sought to compare the clinical effectiveness of lowering LDL cholesterol by means of lipid-lowering therapy for primary prevention of cardiovascular disease among older and younger individuals in a Danish nationwide cohort. METHODS: We included individuals aged ≥50 years who had initiated lipid-lowering therapy from January 1, 2008, to October 31, 2017, had no history of atherosclerotic cardiovascular disease, and had a baseline and a within-1-year LDL cholesterol measurement. We assessed the associated risk of major vascular events among older individuals (≥70 years) by HRs per 1 mmol/L reduction in LDL cholesterol compared with younger individuals (<70 years). RESULTS: For both the 16,035 older and the 49,155 younger individuals, the median LDL cholesterol reduction was 1.7 mmol/L. Each 1 mmol/L reduction in LDL cholesterol in older individuals was significantly associated with a 23% lower risk of major vascular events (HR: 0.77; 95% CI: 0.71-0.83), which was equal to that of younger individuals (HR: 0.76; 95% CI: 0.71-0.80; P value for difference = 0.79). Similar results were observed across all secondary analyses. CONCLUSIONS: Our study supports a relative clinical benefit of lowering LDL cholesterol for primary prevention of major vascular events in individuals aged ≥70 years similarly as in individuals aged <70 years.

Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in Nordic countries: population based cohort analyses.

OBJECTIVE: To investigate the comparative vaccine effectiveness of heterologous booster schedules (ie, three vaccine doses) compared with primary schedules (two vaccine doses) and with homologous mRNA vaccine booster schedules (three vaccine doses) during a period of omicron predominance. DESIGN: Population based cohort analyses. SETTING: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 31 December 2022. PARTICIPANTS: All adults aged ≥18 years who had received at least a primary vaccination schedule of AZD1222 (Oxford-AstraZeneca) or monovalent SARS-CoV-2 wild type (ancestral) strain based mRNA vaccines BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), in any combination. MAIN OUTCOME MEASURES: The main outcome measure was country combined risks of covid-19 related hospital admission and death with covid-19 and additional outcomes of covid-19 related admission to an intensive care unit and SARS-CoV-2 infection. During a period of omicron predominance, these outcomes were compared in those who received a heterologous booster versus primary schedule (matched analyses) and versus those who received a homologous mRNA vaccine booster (weighted analyses). Follow-up was for 75 days from day 14 after the booster dose; comparative vaccine effectiveness was calculated as 1-risk ratio. RESULTS: Across the four Nordic countries, 1 086 418 participants had received a heterologous booster schedule of AZD1222+BNT162b2 or mRNA-1273 and 2 505 093 had received a heterologous booster schedule of BNT162b2+mRNA-1273. Compared with the primary schedule only (two doses), the vaccine effectiveness of heterologous booster schedules comprising AZD1222+BNT162b2 or mRNA-1273 and BNT162b2+mRNA-1273 was 82.7% (95% confidence interval 77.1% to 88.2%) and 81.5% (78.9% to 84.2%) for covid-19 related hospital admission and 95.9% (91.6% to 100.0%) and 87.5% (82.5% to 92.6%) for death with covid-19, respectively. Homologous mRNA booster schedules were similarly associated with increased protection against covid-19 related hospital admission (≥76.5%) and death with covid-19 (≥84.1%) compared with previous primary course vaccination only. When a heterologous booster schedule was compared with the homologous booster schedule, vaccine effectiveness was 27.2% (3.7% to 50.6%) for AZD1222+BNT162b2 or mRNA-1273 and 23.3% (15.8% to 30.8%) for BNT162b2+mRNA-1273 schedules against covid-19 related hospital admission and 21.7% (-8.3% to 51.7%) and 18.4% (-15.7% to 52.5%) against death with covid-19, respectively. CONCLUSION: Heterologous booster schedules are associated with increased protection against severe, omicron related covid-19 outcomes compared with primary course schedules and homologous booster schedules.

Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study.

OBJECTIVE: To estimate the effectiveness of the bivalent mRNA booster vaccines containing the original SARS-CoV-2 and omicron BA.4-5 or BA.1 subvariants as the fourth dose against severe covid-19. DESIGN: Nationwide cohort analyses, using target trial emulation. SETTING: Denmark, Finland, Norway, and Sweden, from 1 July 2022 to 10 April 2023. PARTICIPANTS: People aged ≥50 years who had received at least three doses of covid-19 vaccine (that is, a primary course and a first booster). MAIN OUTCOME MEASURES: The Kaplan-Meier estimator was used to compare the risk of hospital admission and death related to covid-19 in people who received a bivalent Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) BA.4-5 or BA.1 mRNA booster vaccine as a fourth dose (second booster) with three dose (first booster) vaccinated people and between four dose vaccinated people. RESULTS: A total of 1 634 199 people receiving bivalent BA.4-5 fourth dose booster and 1 042 124 receiving bivalent BA.1 fourth dose booster across the four Nordic countries were included. Receipt of a bivalent BA.4-5 booster as a fourth dose was associated with a comparative vaccine effectiveness against admission to hospital with covid-19 of 67.8% (95% confidence interval 63.1% to 72.5%) and a risk difference of -91.9 (95% confidence interval -152.4 to -31.4) per 100 000 people at three months of follow-up compared with having received three doses of vaccine (289 v 893 events). The corresponding comparative vaccine effectiveness and risk difference for bivalent BA.1 boosters (332 v 977 events) were 65.8% (59.1% to 72.4%) and -112.9 (-179.6 to -46.2) per 100 000, respectively. Comparative vaccine effectiveness and risk difference against covid-19 related death were 69.8% (52.8% to 86.8%) and -34.1 (-40.1 to -28.2) per 100 000 for bivalent BA.4-5 booster (93 v 325 events) and 70.0% (50.3% to 89.7%) and -38.7 (-65.4 to -12.0) per 100 000 for BA.1 booster (86 v 286) as a fourth dose. Comparing bivalent BA.4-5 and BA.1 boosters as a fourth dose directly resulted in a three month comparative vaccine effectiveness and corresponding risk difference of -14.9% (-62.3% to 32.4%) and 10.0 (-14.4 to 34.4) per 100 000 people for admission to hospital with covid-19 (802 v 932 unweighted events) and -40.7% (-123.4% to 42.1%) and 8.1 (-3.3 to 19.4) per 100 000 for covid-19 related death (229 v 243 unweighted events). The comparative vaccine effectiveness did not differ across sex and age (

Safety of BA.4-5 or BA.1 bivalent mRNA booster vaccines: nationwide cohort study.

OBJECTIVE: To examine the association between the omicron adapted bivalent mRNA covid-19 booster vaccines received as a fourth dose and risk of adverse events. DESIGN: Nationwide cohort study. SETTING: Denmark. PARTICIPANTS: 2 225 567 adults aged ≥50 years who received three covid-19 vaccine doses during the study period, 1 January 2021 to 10 December 2022. MAIN OUTCOME MEASURES: The main outcome measure was rates of hospital visits for 27 different adverse events in a 28 day main risk period after vaccination with a bivalent omicron adapted mRNA booster vaccine as a fourth dose compared with reference period rates from day 29 after the third or fourth vaccine dose and onward. RESULTS: 1 740 417 adults (mean age 67.8 years, standard deviation 10.7 years) received a bivalent mRNA vaccine as a fourth dose. Fourth dose vaccination with a bivalent mRNA vaccine was not associated with a statistically significant increased rate of any of the 27 adverse outcomes within 28 days (eg, incidence rate ratio of 0.95, 95% confidence interval of 0.87 to 1.04 for ischaemic cardiac events based on 672 v 9992 events during the compared 28 day risk and reference period, respectively), nor when analysed according to age, sex, or vaccine type, or when using alternative analytical approaches. However, post hoc analysis detected signals for myocarditis (statistically significant in female participants), although the outcome was rare and findings were based on few cases. No risk of cerebrovascular infarction was found (incidence rate ratio 0.95, 95% confidence interval 0.87 to 1.05; 644 v 9687 events). CONCLUSIONS: The use of bivalent mRNA vaccines as a fourth vaccine dose against covid-19 was not associated with an increased risk of 27 different adverse events in adults aged ≥50 years.

Safety of heterologous primary and booster schedules with ChAdOx1-S and BNT162b2 or mRNA-1273 vaccines: nationwide cohort study.

OBJECTIVE: To assess the risk of adverse events associated with heterologous primary (two dose) and booster (three dose) vaccine schedules for covid-19 with Oxford-AstraZeneca's ChAdOx1-S priming followed by mRNA vaccines (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) as compared with homologous mRNA vaccine schedules for covid-19. DESIGN: Nationwide cohort study. SETTING: Denmark, 1 January 2021 to 26 March 2022. PARTICIPANTS: Adults aged 18-65 years who received a heterologous vaccine schedule of priming with ChAdOx1-S and one or two mRNA booster doses (with either the BNT162b2 or mRNA-1273 vaccine) were compared with adults who received a homologous BNT162b2 or mRNA-1273 vaccine schedule (ie, two dose v two dose, and three dose v three dose schedule). MAIN OUTCOME MEASURES: The incidence of hospital contacts for a range of adverse cardiovascular and haemostatic events within 28 days after the second or third vaccine dose, comparing heterologous versus homologous vaccine schedules. Secondary outcomes included additional prioritised adverse events of special interest. Poisson regression was used to estimate incidence rate ratios with adjustment for selected covariates. RESULTS: Individuals who had had a heterologous primary vaccine (n=137 495) or a homologous vaccine (n=2 688 142) were identified, in addition to those who had had a heterologous booster (n=129 770) or a homologous booster (n=2 197 213). Adjusted incidence rate ratios of adverse cardiovascular and haemostatic events within 28 days for the heterologous primary and booster vaccine schedules in comparison with the homologous mRNA vaccine schedules were 1.22 (95% confidence interval 0.79 to 1.91) and 1.00 (0.58 to 1.72) for ischaemic cardiac events, 0.74 (0.40 to 1.34) and 0.72 (0.37 to 1.42) for cerebrovascular events, 1.12 (0.13 to 9.58) and 4.74 (0.94 to 24.01) for arterial thromboembolisms, 0.79 (0.45 to 1.38) and 1.09 (0.60 to 1.98) for venous thromboembolisms, 0.84 (0.18 to 3.96) and 1.04 (0.60 to 4.55) for myocarditis or pericarditis, 0.97 (0.45 to 2.10) and 0.89 (0.21 to 3.77) for thrombocytopenia and coagulative disorders, and 1.39 (1.01 to 1.91) and 1.02 (0.70 to 1.47) for other bleeding events, respectively. No associations with any of the outcomes were found when restricting to serious adverse events defined as stay in hospital for more than 24 h. CONCLUSION: Heterologous primary and booster covid-19 vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules. These results are reassuring but given the rarity of some of the adverse events, associations cannot be excluded.

Evaluation of Topical Corticosteroid Use in Pregnancy and Risk of Newborns Being Small for Gestational Age and Having Low Birth Weight.

IMPORTANCE: Topical corticosteroids are frequently used during pregnancy. Limited data have raised concerns about an increased risk of the newborn being small for gestational age (SGA) and having low birth weight, in particular with use of potent to very potent agents during pregnancy. OBJECTIVE: To evaluate whether topical corticosteroid use in pregnancy is associated with increased risks of SGA and low birth weight. DESIGN, SETTING, AND PARTICIPANTS: From a source cohort of 1.1 million pregnancies with individual-level informed data from various registries, this nationwide cohort study identified topical corticosteroid-exposed pregnancies in Denmark from January 1, 1997, to December 31, 2016, for a total of 60 497, that were matched with 241 986 unexposed pregnancies on the basis of propensity scores, including a wide set of baseline characteristics. Data analysis was performed from September 8, 2020, to February 23, 2021. EXPOSURES: Filled prescriptions for topical corticosteroids during pregnancy. MAIN OUTCOMES AND MEASURES: Primary outcomes were SGA and low birth weight. Association between outcomes and exposure was assessed by relative risk ratios (RRs) and absolute risk differences (ARDs). RESULTS: Among the 60 497 matched pregnancies exposed to topical corticosteroids, 5678 (9.4%) of the delivered infants were born SGA compared with 22 634 infants (9.4%) among the matched unexposed pregnancies (RR, 1.00; 95% CI, 0.98-1.03 and ARD, 0.3; 95% CI, -2.3 to 2.9 per 1000 pregnancies). Low birth weight occurred in 2006 (3.3%) of the exposed pregnancies compared with 8675 (3.6%) of the unexposed pregnancies (RR, 0.92; 95% CI, 0.88-0.97 and ARD, -2.7; 95% CI, -4.3 to -1.1 per 1000 pregnancies). Exposure to potent to very potent topical corticosteroids at any amount was not associated with an increased risk of SGA (RR, 1.03; 95% CI, 0.99-1.07) or low birth weight (RR, 0.94; 95% CI, 0.88-1.00). Post hoc analyses did not find a significant increased risk among those receiving large amounts of potent to very potent topical corticosteroids (ie, >200 g throughout pregnancy) compared with unexposed pregnancies (RR, 1.17; 95% CI, 0.95-1.46 for SGA and RR 1.14; 95% CI, 0.81-1.60 for low birth weight). CONCLUSIONS AND RELEVANCE: This large cohort study found no association between topical corticosteroid use in pregnancy and an increased risk of SGA or low birth weight. These results suggest that a moderate to large increase in the risk is unlikely, even when large amounts of potent to very potent topical corticosteroids are used in pregnancy.

Adverse childhood experiences and asthma: trajectories in a national cohort.

OBJECTIVE: Research has linked early adverse childhood experiences (ACEs) with asthma development; however, existing studies have generally relied on parent report of exposure and outcome. We aimed to examine the association of early life ACEs with empirically determined trajectories of childhood asthma risk, using independent register information on both exposures and outcome. METHODS: Based on nationwide registries, we established a study cohort of 466 556 children born in Denmark (1997-2004). We obtained information on ACEs during the first 2 years of life (bereavement, parental chronic somatic and/or mental illness) and childhood asthma diagnosis or medication use from birth through age 10 years from the Danish National Patient and Prescription Registries, respectively. We identified asthma phenotypes using group-based trajectory modelling. We then used multinomial logistic regression to examine the association between early ACEs and asthma phenotypes. RESULTS: We identified four asthma phenotypes: non-asthmatic, early-onset transient, early-onset persistent and late-onset asthma. Girls with early-onset transient asthma (OR 1.13, 95% CI 1.04 to 1.24), early-onset persistent asthma (1.27, 95% CI 1.08 to 1.48) or late-onset asthma (OR 1.28, 95% CI 1.11 to 1.48) vs no asthma were more likely to have early life ACE exposure compared with girls without ACE exposure. Results were similar for boys who also had experienced early life ACEs with ORs of 1.16 (95% CI 1.08 to 1.25), 1.34 (95% CI 1.20 to 1.51) and 1.11 (95% CI 0.98 to 1.25), respectively. CONCLUSION: In a nationwide-population study, we identified three childhood onset asthma phenotypes and found that ACEs early in life were associated with increased odds for each of these asthma phenotypes among both girls and boys.

Association between use of macrolides in pregnancy and risk of major birth defects: nationwide, register based cohort study.

OBJECTIVE: To examine the association between the use of macrolide antibiotics in pregnancy and the risk of major birth defects. DESIGN: Nationwide, register based cohort study. SETTING: Denmark, 1997-2016. PARTICIPANTS: Of 1 192 539 live birth pregnancies, pregnancies during which macrolides had been used (13 019) were compared with those during which penicillin (that is, phenoxymethylpenicillin) had been used (matched in a 1:1 ratio on propensity scores). Other comparative groups were pregnancies when macrolides had been used recently but before pregnancy (matched 1:1) and pregnancies where no antibiotics had been used (matched 1:4). MAIN OUTCOME MEASURES: Association with an outcome of any major birth defect and specific subgroups of birth defects were assessed by relative risk ratios and absolute risk differences. RESULTS: In matched comparisons, 457 infants were born with major birth defects to women who had used macrolides during pregnancy (35.1 per 1000 pregnancies) compared with 481 infants (37.0 per 1000 pregnancies) to women who had used penicillin (relative risk ratio 0.95; 95% confidence interval 0.84 to 1.08), corresponding to an absolute risk difference of -1.8 (95% confidence interval -6.4 to 2.7) per 1000 pregnancies. The risk of major birth defects was not significantly increased for women who had used macrolides during pregnancy compared with those who had used macrolides recently but before becoming pregnant (relative risk ratio 1.00 (95% confidence interval 0.88 to 1.14); absolute risk difference -0.1 (95% confidence interval -4.8 to 4.7) per 1000 pregnancies) or compared with women who did not use any antibiotics (1.05 (0.95 to 1.17); 1.8 (-1.7 to 5.3) per 1000 pregnancies). For all three comparative group analyses and in the analyses of use of individual macrolides, no significant increased risk of specific subgroups of birth defects associated with the use of macrolides was found. CONCLUSIONS: In this nationwide cohort study, the use of macrolide antibiotics in pregnancy was not associated with an increased risk of major birth defects. Analyses of the associated risk of 12 specific subgroups of birth defects with the use of macrolides in pregnancy were not significant.

Fetal safety of chloroquine and hydroxychloroquine use during pregnancy: a nationwide cohort study.

OBJECTIVE: The antimalaria 4-aminoquinoline drugs chloroquine and HCQ are used in the treatment of a wide range of CTDs. Data to inform on the safety of their use in pregnancy are limited. METHODS: In a Danish nationwide cohort study from 1996 through 2016, we identified 4-aminoquinoline-exposed pregnancies from a cohort of 1 240 875 pregnancies to investigate the associated risks of major birth defects, preterm birth, and small size for gestational age (SGA). Distinct study cohorts of propensity-score-matched 4-aminoquinoline-exposed and unexposed pregnancies (in a 1:1 ratio) were established for each outcome analysis. The association with the outcomes was assessed by prevalence odds ratios (ORs) estimated through logistic regression. The associated risks for chloroquine and HCQ were individually assessed through additional analyses. RESULTS: A total of 1487 pregnancies exposed to 4-aminoquinolines (1184 chloroquine- and 303 HCQ-exposed) were identified. Among the 983 pregnancies exposed to 4-aminoquinolines in the first trimester, 34 infants (3.5%) were diagnosed with major birth defects as compared with 36 (3.7%) among the matched unexposed pregnancies (prevalence OR, 0.94; 95% CI: 0.59, 1.52). Exposure to 4-aminoquinolines in pregnancy was neither associated with an increased risk of preterm birth (prevalence OR, 0.97; 95% CI: 0.73, 1.28) or SGA (prevalence OR, 1.18; 95% CI: 0.93, 1.50), compared with unexposed pregnancies. No significant associations between exposure to chloroquine or HCQ individually and risk of the outcomes were identified. CONCLUSION: Among pregnancies exposed to 4-aminoquinolines (chloroquine and HCQ), no increased risk of major birth defects, preterm birth, or SGA was identified.

Maternal life and work stressors during pregnancy and asthma in offspring.

BACKGROUND: Maternal stressors during pregnancy are potential risk factors for asthma in offspring. However, previous studies have been limited by the use of self-reported data focusing on stressors either in private life or at work. This study examined the association between maternal stressors both in private life and at work during pregnancy and asthma in offspring. METHODS: In the Danish National Birth Cohort, 75 156 live-born singletons born during 1996-2002 were identified. Maternal information on job title were available around weeks 12-16 of gestation. Data on maternal bereavement, life-threatening illness, suicide attempt and alcohol or drug abuse of a close relative and offspring childhood asthma (3-10 years of age) were obtained from Danish nationwide registers. Maternal psychosocial work stressors (job control, psychological job demands, emotional job demands, work-related violence and threats of work-related violence) were estimated by the use of job-exposure matrices. The association between maternal stress and childhood asthma was analysed in Cox models adjusted for maternal age, comorbidity and parity. RESULTS: Neither private-life nor work stressors were related to onset of asthma in offspring. Separate analyses by parental atopy or onset of asthma in offspring supported the main findings. CONCLUSIONS: This study does not support an elevated risk of childhood asthma related to exposure to stress during pregnancy.

Association Between Fexofenadine Use During Pregnancy and Fetal Outcomes.

Importance: Fexofenadine hydrochloride is a frequently used drug for treatment of allergic conditions during pregnancy, but the fetal safety of fexofenadine use has not been well studied. Objective: To investigate the risk of adverse fetal outcomes associated with fexofenadine use during pregnancy. Design, Setting, and Participants: A nationwide registry-based cohort study was conducted on pregnancies in Denmark from January 1, 2001, to December 31, 2016. Data analysis was performed from March 21, 2019, to January 29, 2020. From a cohort of 1 287 668 pregnancies, fexofenadine use was compared with cetirizine hydrochloride use during pregnancy, matched in a 1:1 ratio on propensity scores. Distinct study cohorts and exposure time periods were applied according to each outcome analysis. Sensitivity analyses included comparing pregnancies with vs without fexofenadine exposure during pregnancy but with previous use before pregnancy and with loratadine use during pregnancy as additional comparator groups. Exposure: Filled prescription for fexofenadine. Main Outcomes and Measures: Major birth defects and spontaneous abortion. Secondary outcomes were preterm birth, small size for gestational age (SGA), and stillbirth. Logistic regression was used to estimate prevalence odds ratios (ORs) of major birth defects, preterm birth, and SGA, and Cox proportional hazards regression was used to estimate hazard ratios (HRs) of spontaneous abortion and stillbirth. Results: For the analyses of major birth defects and spontaneous abortion, a total of 2962 and 4901 pregnancies with fexofenadine use were included, respectively, matched in a 1:1 ratio with pregnancies with cetirizine use. Mean (SD) age of the fexofenadine cohort for analyses of major birth defects was 30.6 (4.8) years and, for analysis of spontaneous abortion, 30.4 (5.5) years. Infants born with major birth defects occurred in 118 pregnancies (4.0%) with fexofenadine use compared with 112 pregnancies (3.8%) with cetirizine use. Spontaneous abortion occurred in 413 pregnancies (8.4%) with fexofenadine use compared with 439 pregnancies (9.0%) with cetirizine use. Fexofenadine use during pregnancy was not associated with an increased risk of major birth defects (prevalence OR, 1.06; 95% CI, 0.81-1.37) or spontaneous abortion (HR, 0.93; 95% CI, 0.82-1.07) compared with cetirizine use during pregnancy. Preterm birth occurred in 370 pregnancies (7.5%) with fexofenadine use compared with 382 pregnancies (7.7%) with cetirizine use (prevalence OR, 0.97; 95% CI, 0.83-1.12), SGA occurred in 515 pregnancies (10.1%) with fexofenadine use compared with 523 pregnancies (10.2%) with cetirizine use (prevalence OR, 0.98; 95% CI, 0.87-1.12), and a total of 16 pregnancies (0.3%) with fexofenadine use ended in stillbirth compared with 24 pregnancies (0.4%) with cetirizine use (HR, 0.67; 95% CI, 0.36-1.27). Sensitivity analyses of the primary outcomes, including the comparisons of pregnancies with loratadine use and pregnancies unexposed to fexofenadine during pregnancy but with prior use of fexofenadine, showed similar results. Conclusions and Relevance: Use of fexofenadine during pregnancy does not appear to be associated with an increased risk of adverse fetal outcomes.

Desloratadine Use During Pregnancy and Risk of Adverse Fetal Outcomes: A Nationwide Cohort Study.

BACKGROUND: Desloratadine is a frequently used drug for the treatment of allergic disorders, which often also require treatment during pregnancy. However, information on the fetal safety of desloratadine use during pregnancy is limited. OBJECTIVE: To investigate the association between desloratadine use during pregnancy and adverse fetal outcomes. METHODS: From a cohort of 1,287,668 pregnancies identified in the Danish nationwide registries in the study period 2001 to 2016, users of desloratadine and loratadine during pregnancy were matched in a 1:1 ratio based on propensity scores to compare the risk of adverse fetal outcomes. We compared the risk of the primary outcomes major birth defects (among a total of 3348 pregnancies) and spontaneous abortion (5498 pregnancies) and the secondary outcomes preterm birth (5280 pregnancies), small size for gestational age (SGA) for birth weight (5436 pregnancies), and stillbirth (6776 pregnancies). Logistic regression was used to estimate the prevalence odds ratio (OR) of major birth defects, preterm birth, and SGA, and Cox regression to estimate the hazard ratio (HR) of spontaneous abortion and stillbirth. Sensitivity analyses included comparing with cetirizine use in pregnancy and with pregnancies unexposed to desloratadine but with prior use as additional comparator groups. RESULTS: Use of desloratadine in pregnancy was not associated with a significant increased risk of major birth defects (prevalence OR, 1.07; 95% confidence interval [CI], 0.77-1.50), spontaneous abortion (HR, 1.15; 95% CI, 0.96-1.37), preterm birth (prevalence OR, 0.84; 95% CI, 0.67-1.05), SGA (prevalence OR, 0.97; 95% CI, 0.80-1.16), or stillbirth (HR, 0.91; 95% CI, 0.31-2.70) compared with loratadine use in pregnancy. Sensitivity analyses, including those with the use of additional comparator groups, showed similar results. CONCLUSION: Use of desloratadine during pregnancy was not associated with a statistically significant increased risk of adverse fetal outcomes as compared with loratadine. Results indicate that the fetal safety profile of desloratadine is similar to the currently recommended second-generation antihistamines during pregnancy.

Evaluation of Association Between Oral and Topical Terbinafine Use in Pregnancy and Risk of Major Malformations and Spontaneous Abortion.

Importance: Terbinafine is a commonly used antifungal agent, but safety data of its use in pregnancy are limited. Objective: To examine the association between oral and topical terbinafine exposure in pregnancy and the risk of major malformations and spontaneous abortion. Design, Setting, and Participants: A nationwide, registry-based cohort study was conducted in Denmark from January 1, 1997, to December 31, 2016, in a cohort of 1 650 649 pregnancies. Data analysis was performed from July 11 to October 20, 2019. Pregnancies were matched on propensity scores comparing oral terbinafine exposed vs unexposed (1:10 ratio), topical terbinafine exposed vs unexposed (1:10), and oral vs topical terbinafine exposed (1:1). Exposures: Filled prescriptions for oral or topical terbinafine. Main Outcomes and Measures: Logistic regression was used to compute prevalence odds ratios for the primary outcome of major malformations and Cox proportional hazards regression was used to compute hazard ratios for the secondary outcome of spontaneous abortion. Results: Based on a cohort of 1 650 649 pregnancies, oral terbinafine-exposed (n = 891 pregnancies; mean [SD] age, 30.4 [6] years) and topical terbinafine-exposed (n = 3174; mean [SD] age, 29.5 [5.4] years) pregnancies were identified; up to a total of 40 650 unexposed pregnancies were included for the matched outcome analyses. In propensity-matched comparisons of the risk of major malformations, the prevalence odds ratios were 1.01 (95% CI, 0.63-1.62) for oral terbinafine-exposed vs unexposed pregnancies (absolute risk difference [ARD], 0.04%; 95% CI, -1.69% to 1.76%), 1.08 (95% CI, 0.81-1.44) for topical terbinafine-exposed vs unexposed pregnancies (ARD, 0.26%; 95% CI, -0.73% to 1.26%), and 1.18 (95% CI, 0.61-2.29) for oral vs topical terbinafine-exposed pregnancies (ARD, 0.59%; 95% CI, -1.71% to 2.88%). For the risk of spontaneous abortion, the hazard ratios were 1.06 (95% CI, 0.86-1.32) for oral terbinafine-exposed vs unexposed pregnancies (ARD, 0.13%; 95% CI, -1.97% to 2.24%), 1.04 (95% CI, 0.88-1.21) for topical terbinafine-exposed vs unexposed pregnancies (ARD, 0.17%; 95% CI, -0.64% to 0.98%), and 1.19 (95% CI, 0.84-1.70) for oral vs topical terbinafine-exposed (ARD, 1.13%; 95% CI, -2.23% to 4.50%) pregnancies. Conclusions and Relevance: Among pregnancies exposed to oral or topical terbinafine, no increased risk of major malformations or spontaneous abortion was identified.

Association Between Fetal Safety Outcomes and Exposure to Local Podophyllotoxin During Pregnancy.

Importance: Podophyllotoxin is an antimitotic agent primarily used in the local treatment of anogenital warts. Data that enable the assessment of the fetal safety of podophyllotoxin use during pregnancy are lacking. Objective: To investigate the association between local podophyllotoxin exposure during pregnancy and risk of adverse fetal outcomes. Design, Setting, and Participants: This cohort study obtained individual-level pregnancy data from various nationwide registries in Denmark from the study period of January 1, 1997, through December 31, 2016, resulting in a cohort of 1 650 649 pregnancies. Pregnancies with multiple records on overlapping dates and pregnancy records with implausible or missing information on gestational age were excluded. Local podophyllotoxin-exposed pregnancies were compared with unexposed pregnancies and matched in a 1:10 ratio according to propensity scores on a wide set of baseline characteristics. Five distinct study cohorts were constructed, one for each outcome analysis. Sensitivity analyses included a comparison of podophyllotoxin-exposed pregnancies with pregnancies with podophyllotoxin use only before pregnancy onset. Data analyses were performed from April 27, 2019, to June 26, 2019. Exposures: Filled prescription for local podophyllotoxin. Main Outcomes and Measures: Primary outcomes were major birth defects and spontaneous abortions. Secondary outcomes were preterm births, small-for-gestational-age (SGA) size, and stillbirths. Logistic regression was used to estimate the prevalence odds ratios (ORs) of major birth defects, preterm births, and SGA size, and Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) of spontaneous abortions and stillbirths. Results: This study included 9229 pregnancies (mean [SD] maternal age at pregnancy onset, 27.7 [5.2] years) for the analyses of major birth defects and 18 590 pregnancies (mean [SD] maternal age at pregnancy onset, 26.4 [6.0] years) for the analyses of spontaneous abortions. Among the podophyllotoxin-exposed pregnancies, 29 infants (3.5%) were diagnosed with major birth defects, compared with 286 (3.4%) among the unexposed pregnancies. A total of 141 podophyllotoxin-exposed pregnancies (8.3%) ended in spontaneous abortion, compared with 1626 (9.6%) among the unexposed pregnancies. No statistically significant associations were found between podophyllotoxin exposure during pregnancy and major birth defects (prevalence odds ratio [OR], 1.02 95% CI, 0.69-1.50), spontaneous abortions (HR, 0.87; 95% CI, 0.73-1.04), preterm births (prevalence OR, 1.08; 95% CI, 0.86-1.35), SGA size (prevalence OR, 1.01; 95% CI, 0.85-1.22), or stillbirths (HR, 0.58; 95% CI, 0.18-1.86). Sensitivity analyses of the primary outcomes achieved similar results. Conclusions and Relevance: Findings from this study suggest that podophyllotoxin use during pregnancy may be safe, as it did not appear to be associated with an increased risk of adverse fetal outcomes. These findings may help guide clinicians, patients, and drug regulatory authorities when prescribing podophyllotoxin.