Paediatric and perinatal epidemiology最新文献

Background: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking.

Objectives: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS.

Methods: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR.

Results: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02).

Conclusions: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.

Background: The COVID-19 pandemic has affected children and adolescents in several ways, including worsened mental health, improvement of asthma, and increases in diabetes ketoacidosis. Less is known about how medication use in children and adolescents has been affected by the pandemic.

Objectives: To explore how the COVID-19 pandemic affected drug utilisation in children and adolescents in Norway, Sweden, and Italy, by child age.

Methods: We conducted a longitudinal drug utilisation study among all children and adolescents (<18 years old) in Norway and Sweden and a nationwide paediatric database covering 3% of the paediatric population in Italy. We conducted an interrupted time-series analysis from January 2018 to December 2021, with March 2020 as the interruption point. Dispensing or prescription rates of antidepressants, anxiolytics, sleep medications, attention-deficit/hyperactivity disorder (ADHD) medications, insulin, and asthma medications were examined.

Results: The study population in January 2018 consisted of 3,455,521 children and adolescents (136,188 from Italy, 1,160,431 from Norway, and 2,158,902 from Sweden). For sleep medications and insulin, there were only minor changes in level or trend in some age groups after March 2020. For asthma medications, the pandemic was associated with an immediate decrease in dispensing in Norway and Sweden (range of change in level: -19.2 to -3.7 dispensings per 1000 person-months), and an increasing trend in all countries afterward (range of change in trend: 0.3-6.4 dispensings per 1000 person-months), especially for the youngest age groups. Among adolescents, the pandemic was associated with an increased trend for ADHD medications, antidepressants, and anxiolytics in Norway and Sweden, but not in Italy.

Conclusions: The increasing trend of psychotropic medication dispensing, especially among adolescents after the start of the pandemic, is concerning and should be investigated further. Aside from a temporary effect on asthma medication dispensing, the pandemic did not greatly affect the dispensing of the medications investigated.

Background: The increasing and prevalent use of gabapentin among pregnant people highlights the necessity to assess its neonatal safety.

Objectives: This study aimed to investigate the foetal safety of gabapentin during pregnancy using a cohort study and scoping review with a meta-analysis of published evidence.

Methods: We conducted a population-based cohort study using the Manitoba health databases between 1995 and 2019. We examined the association between gabapentin use during pregnancy and the prevalence of major congenital malformations, cardiac and orofacial malformations, and neonatal intensive care unit (NICU) admissions using multivariate regression models. We searched the literature in MEDLINE and EMBASE databases from inception to October 2022 to identify relevant observational studies and conducted a meta-analysis using random-effects models, including our cohort study results.

Results: Of the 289,227 included pregnancies, 870 pregnant people were exposed to gabapentin. Gabapentin exposure during the First trimester was not associated with an increased risk of any malformations (adjusted relative risk [aRR]) 1.16 (95% confidence interval [CI] 0.92, 1.46), cardiac malformations (aRR 1.29, 95% CI 0.72, 2.29), orofacial malformations (aRR 1.37, 95% CI 0.50, 3.75), and major congenital malformations (aRR 1.00, 95% CI 0.73, 1.36). whereas exposure during any trimester was associated with an increased NICU admission risk (aRR, 1.99, 95% CI 1.70, 2.32). The meta-analysis of unadjusted results revealed an increased risk of major congenital malformations (RR 1.44, 95% CI 1.28, 1.61, I² = 0%), cardiac malformations (RR 1.66, 95% CI 1.11, 2.47, I² = 68%), and NICU admissions (RR 3.15, 95% CI 2.90, 3.41, I² = 10%), and increased trend of orofacial malformations (RR 1.98, 95% CI 0.79, 5.00, I² = 0%).

Conclusions: Gabapentin use was associated with an increased risk of NICU admissions in the cohort study and pooled meta-analysis. Clinicians should prescribe gabapentin with caution during pregnancy and further studies are warranted.

Background: Breastfeeding information stored within electronic health records (EHR) has recently been used for pharmacoepidemiological research, however the data are primarily collected for clinical care.

Objectives: To characterise breastfeeding information recorded in structured fields in EHR during infant and postpartum health care visits, and to assess the validity of lactation status based on EHR data versus maternal report at research study visits.

Methods: We assessed breastfeeding information recorded in structured fields in EHR from one health system for a subset of 211 patients who were also enrolled in a study on breast milk composition between 2014 and 2017 that required participants to exclusively breastfeed their infants until at least 1 month of age. We assessed the frequency of breastfeeding information in EHR during the first 12 months of age and compared lactation status based on EHR with maternal report at 1 and 6-month study visits (reference standard).

Results: The median number of breastfeeding records in the EHR per infant was six (interquartile range 3) with most observations clustering in the first few weeks of life and around well-infant visits. At the 6-month study visit, 93.8% of participants were breastfeeding and 80.1% were exclusively breastfeeding according to maternal report. Sensitivity of EHR data for identifying ever breastfeeding was at or near 100%, and sensitivity for identifying ever exclusive breastfeeding was 98.0% (95% CI: 95.0%, 99.2%). Sensitivities were 97.3% (95% CI: 93.9%, 98.9%) for identifying any breastfeeding and 94.4% (95% CI: 89.7%, 97.0%) for exclusive breastfeeding, and positive predictive values were 99.5% (95% CI: 97.0%, 99.9%) for any breastfeeding and 95.0% (95% CI: 90.4%, 97.4%) for exclusive breastfeeding.

Conclusions: Breastfeeding information in structured EHR fields have the potential to accurately classify lactation status. The validity of these data should be assessed in populations with a lower breastfeeding prevalence.

Background: Past research on the safety of prenatal exposure to medications has focused on maternal use during gestation, with limited research into the potential effects of paternal use during the spermatogenic period preceding conception. Knowing the most common medications used by fathers around the time of conception can inform research priorities in this field.

Objectives: To identify the most common medications dispensed to fathers in the preconception period.

Methods: Within the MarketScan research database of commercially insured individuals in the United States from 2011 to 2020, we identified pregnancies, estimated the date of conception, linked each pregnancy to the father using family enrolment information and required minimum enrolment period and prescription benefits. Then, we described the use of prescription medications by the father during the 90 days before conception based on pharmacy dispensation claims.

Results: Of 4,437,550 pregnancies, 51.6% were linked with a father. Among the 1,413,762 pregnancies connected with a father that also met the inclusion criteria, the most common classes of medications dispensed were psychotropics (8.66%), antibiotics (7.21%), and analgesics (6.82%). The most frequently dispensed medications were amoxicillin (3.75%), azithromycin (3.15%), fluticasone (2.70%) and acetaminophen/hydrocodone (2.70%). Some fathers filled prescriptions for medications associated with foetal embryopathy when used by the mother, including mycophenolate (0.04%), methotrexate (0.03%) and isotretinoin (0.02%).

Conclusions: More than a third of fathers filled at least one prescription medication in the preconception period, and several of them are known to be embryotoxic, emphasizing the necessity for further investigation into the potential teratogenicity of paternal exposure.

Background: In observational medication pregnancy safety studies, children are often followed from birth to 1 year of age. However, some major congenital malformations (MCM) may take longer to diagnose.

Objectives: We aimed to investigate the proportion of children with detected MCMs at different lengths of follow-up and compare them to the proportion detected at 1 year after birth.

Methods: This population-based register study included all singleton children liveborn in Sweden from 2006 to 2016. MCM were identified by ICD-10 codes in the Medical Birth Register and National Patient Register, aligned to the EUROCAT classification system. Cumulative proportion of children with detected MCM at birth, 90 days, 1, 2, and 3 years was calculated and compared between children born preterm and at term.

Results: In 1,138,113 liveborn children, the cumulative proportion of children with a detected MCM increased from 1.9% at birth to 3.1%, 3.9%, 4.4% and 4.7% at 90 days, 1, 2, and 3 years after birth, respectively, and varied by MCM subgroup. MCMs of the eye, ear-face-neck, nervous system and genitals were detected with the longest delay, with 31%-59% more detected at 3- versus 1-year follow-up. Compared to children born at term, the proportion of children with any MCM was 2.5 times higher amongst preterm children, with a higher proportion detected over the first 90 days for most MCM subgroups.

Conclusions: The proportion of children with a detected MCM varied by MCM subgroup and follow-up time. In pharmacoepidemiology studies of medication safety in pregnancy using Swedish national data, the length of child follow-up should be chosen in accordance with the expected age at detection if a specific subgroup of MCM is under investigation, for example, eye and genital MCM require longer follow-up for detection than abdominal wall and digestive system MCM. However, in most circumstances, 1 year of follow-up is sufficient.

Background: Low-dose aspirin prophylaxis is recommended for women at risk of preeclampsia. Capturing aspirin prophylaxis within administrative databases can be challenging since it is an over-the-counter medication. The Better Outcome Registry and Network (BORN) database, a perinatal health registry in Ontario, Canada, includes a formal variable that captures aspirin prophylaxis for preeclampsia. This variable has not been formally validated.

Objectives: To assess the accuracy of the aspirin prophylaxis variable in the BORN database against an electronic medical record (EMR).

Methods: This validation study comprised 200 randomly selected women who had a livebirth at St. Michael's Hospital (SMH) in Toronto, Ontario, from January 2018 to July 2022. Recorded aspirin prophylaxis in pregnancy and maternal sociodemographic characteristics were independently extracted by two abstractors. Accuracy of aspirin prophylaxis use in the BORN database was compared to that in the SMH EMR, expressed as sensitivity, specificity, positive (PPV) and negative predictive values (NPV), Cohen's kappa (κ), and overall percent agreement, with 95% confidence intervals (CI). Sensitivity analyses were performed to account for missing or unclear aspirin prophylaxis use.

Results: Among 200 women, 24 (12.0%) received aspirin prophylaxis - 12.5% within the SMH EMR and 8.0% in the BORN database. Women using aspirin were older (37.0 vs 33.0 years) and had higher median gravidity (3 vs. 2). Sensitivity and specificity of the BORN aspirin prophylaxis variable were 62.5% (95% CI 40.6, 81.2) and 100.0% (95% CI 97.3, 100.0), respectively. The corresponding positive and negative predictive values were 100.0% (95% CI 78.2, 100.0), and 93.8% (95% CI 88.6, 97.1), respectively. Cohen's κ was 0.74 (95% CI 0.58, 0.90), and overall percent agreement was 94.4% (95% CI 87.1, 100.0).

Conclusions: Aspirin use within the BORN database, based on a standard variable field, appears accurate enough for the potential use in epidemiological studies of aspirin prophylaxis for preeclampsia or as a covariate in related studies.

Background: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women.

Objective: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data.

Methods: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI).

Results: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56).

Conclusions: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy.