Prenatal and postnatal exposures to endocrine disrupting chemicals and timing of pubertal onset in girls and boys: a systematic review and meta-analysis.

BACKGROUND: Globally, the ages at pubertal onset for girls and boys have been decreasing during recent decades, partly attributed to excess body fat accumulation. However, a growing body of literature has recognized that endocrine disrupting chemicals (EDCs) may play an important role in this global trend, but the association has not yet been fully established. OBJECTIVE AND RATIONALE: EDCs can interfere with normal hormone function and metabolism and play a role in pubertal onset. We aimed to systematically identify and evaluate the current evidence on the timing of pubertal onset in girls and boys following prenatal or postnatal exposures to xenobiotic EDCs. SEARCH METHODS: Following PRISMA guidelines, we performed a systematic literature search of original peer-reviewed publications in the PubMed database through a block search approach using a combination of index MeSH and free text search terms. Publications were considered if they covered biomarkers of prenatal or postnatal exposures to xenobiotic EDCs (European Commission's list of category 1 EDCs) measured in maternal or child biospecimen and pubertal onset defined by the progression of the following milestones (and assessed in terms of the following measures): menarche (age), thelarche (Tanner staging) and pubarche (Tanner staging), in girls, and genital stage (Tanner staging), testicular volume (ml) and pubarche (Tanner staging), in boys. OUTCOMES: The literature search resulted in 703 references, of which we identified 52 publications fulfilling the eligibility criteria for the qualitative trend synthesis and 23 publications for the meta-analysis. The qualitative trend synthesis provided data on 103 combinations of associations between prenatal or postnatal exposure to EDC compounds groups and puberty outcomes and the meta-analysis enabled 18 summary risk estimates of meta-associations. WIDER IMPLICATIONS: Statistically significant associations in the qualitative trend synthesis suggested that postnatal exposure to phthalates may be associated with earlier thelarche and later pubarche. However, we did not find consistent evidence in the meta-analysis for associations between timing of pubertal onset in girls and boys and exposures to any of the studied xenobiotic EDCs. We were not able to identify specific pre- or postnatal windows of exposure as particularly critical and susceptible for effects of EDCs. Current evidence is subject to several methodological challenges and inconsistencies and evidence on specific exposure-outcome associations remains too scarce to firmly confirm EDC exposure as a risk factor for changes in age of pubertal onset in the general child population. To create a more uniform foundation for future comparison of evidence and to strengthen pooled studies, we recommend the use of more standardized approaches in the choice of statistical analyses, with exposure transformations, and in the definitions and assessments of puberty outcomes. The impact of mixtures of EDC exposures on the association also remains unestablished and would be valuable to elucidate for prenatal and postnatal windows of exposure. Future large, longitudinal epidemiological studies are needed to clarify the overall association.

Cytokine concentration across the stratum corneum in atopic dermatitis and healthy controls.

Tape stripping is a promising technique for assessment of epidermal biomarkers in inflammatory skin diseases. However, to facilitate its implementation in the clinical practice, a thorough validation regarding sampling strategy is needed. Knowledge of biomarkers variation in concentration across stratum corneum is scarce. Therefore, this study aimed to assess the variability of cytokines across stratum corneum using tape stripping technique by consecutive application of 21 adhesive tapes (D-squame) to lesional and non-lesional skin from 15 patients with atopic dermatitis (AD) and 16 healthy controls. Concentration of cytokines (IL-1α, IL-1b, IL-5, IL-18, IFN-γ, CCL17, CCL22, CCL27, CXCL8, CXCL10, TNF-α, TSLP, VEGFA) was determined in five different depths, using multiplex immunoassay. Comparing tape 4 with tape 21, no cytokine changed significantly in concentration in AD lesional skin. In AD non-lesional skin a small decrease was found for CCL17, CXCL8 and CXCL10. For healthy controls, a decrease was found for IL-1a, IL-1b, VEGFA and an increase for IL-18. Differences were found between AD skin and healthy control skin. Concentration of cytokines was stable across stratum corneum, indicating that sampling of only one tape from the stratum corneum is reliable in reflecting the overall cytokine milieu. Differences between AD and healthy skin confirm robustness of tape stripping for measuring cytokine levels.

Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre.

BACKGROUND: Management of moderate-to-severe atopic dermatitis (AD) frequently requires treatment with systemic therapies. Dupilumab is the first biological agent approved for treatment of moderate-to-severe AD. Although promising results have appeared in clinical trials, real-life data on efficacy and safety are lacking. OBJECTIVES: To assess effectiveness and safety of treatment with dupilumab in the real-life clinical setting at a Danish tertiary referral centre. METHODS: All patients with AD treated with dupilumab from October 2017 to October 2018 at Bispebjerg Hospital, Denmark, were included in the study. Patients were evaluated three times: at treatment initiation and at 1 and 3 months after first dupilumab injection. At each visit, disease activity was assessed by severity score (Eczema Area and Severity Index, EASI), patient-reported outcomes (Dermatology Life Quality Index, DLQI, pruritus and sleep score) and serological markers [immunoglobulin (Ig)E, eosinophil count and lactate dehydrogenase (LDH)]. RESULTS: A total of 43 patients were included in the study. The mean reduction in EASI score from baseline was 19.6 points (72.4%) at 1-month and 22.6 points (76.7%) at 3-month follow-up. EASI, DLQI, pruritus score, sleep score, IgE and LDH were all statistically significantly reduced between baseline and 1- and 3-month follow-up. Mean reductions in EASI score and LDH at 3-month follow-up were significantly correlated (P = 0.003). One patient (2.3%) discontinued treatment due to side-effects, and seven patients (18.4%) developed conjunctivitis during the study period. CONCLUSION: The effectiveness and safety of dupilumab treatment in a real-life clinical setting are comparable to that of phase 3 clinical trials. LDH is suggested as a potential serological marker predictive of treatment response.

Factors influencing prognosis for occupational hand eczema: new trends.

BACKGROUND: Variables traditionally reported to influence the prognosis of occupational hand eczema (OHE) are atopic dermatitis (AD) and contact sensitization. However, recent studies indicate that lifestyle factors may be of major importance. OBJECTIVES: To identify factors influencing the prognosis in a cohort of patients with recognized OHE. METHODS: In this register-based cohort study, individuals with hand eczema recognized as occupational disease in the period January 2010-December 2011 were identified using files from Labor Market Insurance Denmark and included in the study. At baseline, information on sex, age, occupation, wet work, AD and contact sensitization was collected. In 2015 participants received a questionnaire with questions about lifestyle factors, current occupation and healing of OHE. RESULTS: In total, 2703 patients received the questionnaire; 1491 responded to the question about healing of OHE and were included in the study. Altogether, 19·3% of patients reported complete healing at follow-up. Current tobacco smoking and a high level of stress were factors inversely associated with healing of hand eczema (P < 0·001 and P = 0·030, respectively), while a high level of exercise was significantly related to healing of eczema (P = 0·011). Change of profession was a favourable prognostic factor, while age, sex, AD, contact sensitization and education did not significantly influence prognosis. CONCLUSIONS: Traditionally important risk factors such as AD and contact sensitization had no marked influence on prognosis, while lifestyle factors were of major importance. Our findings indicate that risk factors may vary over time, allowing for new perspectives on prevention. What's already known about this topic? Occupational hand eczema has a relapsing course and a poor overall prognosis. Atopic dermatitis and contact sensitization have previously been reported as risk factors for a poor prognosis. What does this study add? The results indicate that lifestyle factors are of importance for the prognosis of occupational hand eczema. Traditionally reported risk factors such as atopic dermatitis and contact sensitization do not currently influence prognosis.

Risk of incarceration in children with inguinal hernia: a systematic review.

BACKGROUND: Surgical repair is recommended for all children with inguinal hernia due to fear of incarceration. The aim of this study was to assess the risk of incarceration and strangulation of inguinal hernias in children treated with delayed surgery or no surgery. METHODS: Systematic searches were conducted in three databases. We included studies reporting on children with inguinal hernia, with the majority ≤ 10 years old. The interventions were non-acute inguinal hernia surgery or no surgery. The main outcomes were incarceration and strangulation. Secondary outcomes were postoperative complications. Randomized controlled trials, non-randomized controlled trials, and observational studies were included. RESULTS: We included 22 studies with 14,959 children. All studies reported on elective repairs. None of the studies specifically reported on watchful waiting. Of the studies reporting wait time as mean or median, the median wait time was 46 days (range 1-552). The crude incarceration rate across the included studies was 7% for all children and 11% for preterm children. The testicular atrophy rate was 1% and the recurrence rate was 1%. CONCLUSIONS: The risk of incarceration in children awaiting inguinal hernia surgery is substantial. In general, we cannot support delaying surgery unnecessarily. However, there may be benefits of delaying surgery in individual cases. In such cases, the surgeon should assess if the benefits may overrule the risk of incarceration.

Associations between social cognition, skills, and function and subclinical negative and positive symptoms in 22q11.2 deletion syndrome.

BACKGROUND: Identification of the early signs of schizophrenia would be a major achievement for the early intervention and prevention strategies in psychiatry. Social impairments are defining features of schizophrenia. Impairments of individual layers of social competencies are frequently described in individuals with 22q11.2 deletion syndrome (22q11.2DS), who have high risk of schizophrenia. It is unclear whether and to what extent social impairments associate with subclinical negative and positive symptoms in 22q11.2DS, and which layer of social impairments are more correlated with schizophrenia-related symptoms. The aims of this study were to conduct a comprehensive investigation of social impairments at three different levels (function, skill, and cognition) and their interrelationship and to determine to what degree the social impairments correlate to subclinical levels of negative and positive symptoms, respectively, in a young cohort of 22q11.2DS not diagnosed with schizophrenia. METHODS: The level of social impairment was addressed using questionnaires and objective measures of social functioning (The Adaptive Behavior Assessment System), skills (Social Responsiveness Scale), and cognition (The Awareness of Social Inference Test and CANTAB Emotional Recognition Task), and the presence of subclinical symptoms of schizophrenia were evaluated using the Structured Interview for Prodromal Syndromes in a cross-sectional case-control study of 29 cases and 29 controls, aged 12 to 25 years. Association between social impairment and negative and positive symptoms levels was examined in cases only. RESULTS: Subjects with 22q11.2DS were highly impaired in social function, social skills, and social cognition (p ≤ 6.2 × 10-9) relative to control peers and presented with more negative (p = 5.8 × 10-11) and positive (p = 7.5 × 10-4) symptoms. In particular, social functional and skill levels were highly associated with notably subclinical negative symptoms levels. CONCLUSIONS: This study shows strong correlations between levels of social impairments and subclinical negative and positive symptoms. However, longitudinal studies are required to show if social impairments represent early disease manifestations. If parental or self-reporting suggests severe social impairment, it should advocate for clinical awareness not only to social deficits per se but also of potential subclinical psychosis symptoms.

Development of a grinding-specific performance test set-up.

The aim of this study was to develop a performance test set-up for America's Cup grinders. The test set-up had to mimic the on-boat grinding activity and be capable of collecting data for analysis and evaluation of grinding performance. This study included a literature-based analysis of grinding demands and a test protocol developed to accommodate the necessary physiological loads. This study resulted in a test protocol consisting of 10 intervals of 20 revolutions each interspersed with active resting periods of 50 s. The 20 revolutions are a combination of both forward and backward grinding and an exponentially rising resistance. A custom-made grinding ergometer was developed with computer-controlled resistance and capable of collecting data during the test. The data collected can be used to find measures of grinding performance such as peak power, time to complete and the decline in repeated grinding performance.

Novel alkali earth borohydride Sr(BH4)2 and borohydride-chloride Sr(BH4)Cl.

Two novel alkali earth borohydrides, Sr(BH4)2 and Sr(BH4)Cl, have been synthesized and investigated by in-situ synchrotron radiation powder X-ray diffraction (SR-PXD) and Raman spectroscopy. Strontium borohydride, Sr(BH4)2, was synthesized via a metathesis reaction between LiBH4 and SrCl2 by two complementary methods, i.e., solvent-mediated and mechanochemical synthesis, while Sr(BH4)Cl was obtained from mechanochemical synthesis, i.e., ball milling. Sr(BH4)2 crystallizes in the orthorhombic crystal system, a = 6.97833(9) Å, b = 8.39651(11) Å, and c = 7.55931(10) Å (V = 442.927(10) Å(3)) at RT with space group symmetry Pbcn. The compound crystallizes in α-PbO2 structure type and is built from half-occupied brucite-like layers of slightly distorted [Sr(BH4)6] octahedra stacked in the a-axis direction. Strontium borohydride chloride, Sr(BH4)Cl, is a stoichiometric, ordered compound, which also crystallizes in the orthorhombic crystal system, a = 10.8873(8) Å, b = 4.6035(3) Å, and c = 7.4398(6) Å (V = 372.91(3) Å(3)) at RT, with space group symmetry Pnma and structure type Sr(OH)2. Sr(BH4)Cl dissociates into Sr(BH4)2 and SrCl2 at ~170 °C, while Sr(BH4)2 is found to decompose in multiple steps between 270 and 465 °C with formation of several decomposition products, e.g., SrB6. Furthermore, partly characterized new compounds are also reported here, e.g., a solvate of Sr(BH4)2 and two Li-Sr-BH4 compounds.

Absence of 'over-the-counter' medicinal products in on-line prescription records: a risk factor of overlooking interactions in the elderly.

PURPOSE: To assess possible origins of harmful interactions in elderly patients arising from the current absence of information on over-the-counter (OTC) medicines in the Danish 'on-line prescription record'. METHODS: Information on current use of prescription drugs and OTC medicinal products (non-prescription drugs, herbal medicine, dietary supplements, and others) was collected by home visit interviews. The latter OTC products were not listed in an on-line prescription record that covered the previous two years. Information on interactions between OTC medicines and between OTC products and prescription drugs was obtained from the Danish National Drug Interaction Database. RESULTS: Of the 309 patients recruited (median age 75 years, interquartile range (IQR) 70-81), 229 (74%) used 568 OTC medicines not listed in the Danish 'on-line prescription record', amongst which we identified 166 potential interactions - between OTC treatments or between OTC and prescription drugs. Fifty percent of patients taking OTC medicines were exposed to potential interactions, i.e. one to three instances per patient. Twenty-five percent of patients exposed to interactions experienced interaction listed as 'Can be used with certain precautions'. CONCLUSION: The absence of information on OTC products in an on-line prescription record entails a risk of overlooking interactions in elderly patients. Such products should be included in on-line medication records to prevent adverse effects from interactions. However, online medication records are not available in all countries and as inclusion of data on OTC drugs seem not to be feasible presently. Still, it is highly recommended that the patient's drug list is reviewed on a regular basis.

Inverse relationship between the complexity of midfoot kinematics and muscle activation in patients with medial tibial stress syndrome.

Medial tibial stress syndrome is a common overuse injury characterized by pain located on the medial side of the lower leg during weight bearing activities such as gait. The purpose of this study was to apply linear and nonlinear methods to compare the structure of variability of midfoot kinematics and surface electromyographic (SEMG) signals between patients with medial tibial stress syndrome and healthy controls during gait. Fourteen patients diagnosed with medial tibial stress syndrome and 11 healthy controls were included from an orthopaedic clinic. SEMG from tibialis anterior and the soleus muscles as well as midfoot kinematics were recorded during 20 consecutive gait cycles. Permuted sample entropy and permutation entropy were used as a measure of complexity from SEMG signals and kinematics. SEMG signals in patients with medial tibial stress syndrome were characterized by higher structural complexity compared with healthy controls (p<0.001) while it was the opposite for the midfoot kinematics (p=0.01). Assessing the complexity of midfoot kinematics and SEMG activation pattern enabled a precise characterization of gait in patients with medial tibial stress syndrome. The reported inverse relationship in foot kinematics and SEMG complexity most likely point towards separated control processes governing gait variability.

Non-linear analysis of the structure of variability in midfoot kinematics.

INTRODUCTION: Evaluation of structural variability in biological time series through measures such as sample entropy (SaEn) has provided important information in neurology and cardiology. This has contributed to the development of the "loss of complexity hypothesis" where high variability has been described as healthy flexibility and low variability associated with pathology. The purpose of this study was to calculate sample entropy (SaEn) to establish normal values of non-linear variability and to examine which factors are associated with SaEn in midfoot kinematics. METHOD: Static foot posture was measured using Foot Posture Index. A video sequence analysis system was used to quantify midfoot kinematics during walking in the sagittal plane. SaEn was calculated for navicular drop during stand phase as an expression of the dynamic complexity. RESULTS: A significant difference was observed between the three major foot types and between genders (p<0.001). Mean SaEn in women were 1.10+/-0.19 (supinated foot posture), 0.96+/-0.17 (neutral foot posture) and 0.77+/-0.16 (pronated foot posture) and 1.25+/-0.24 (supinated foot posture), 1.06+/-0.23 (neutral foot posture) and 0.86+/-0.19 (pronated foot posture) in males. The regression model showed that foot posture and dynamic navicular drop (dND) were both associated with SaEn. CONCLUSION: This study confirmed that non-linear analysis is of relevance in the interpretation of kinematic data. Pronated foot posture, large navicular drop and women were characterized by low values of non-linear variability. Future studies should investigate if measurements of SaEn are capable of identifying subjects with an increased risk of injury.

Perspectives for clinical measures of dynamic foot function-reference data and methodological considerations.

Several studies have investigated if static posture assessments qualify to predict dynamic function of the foot showing diverse outcomes. However, it was suggested that dynamic measures may be better suited to predict foot-related overuse problems. The purpose of this study was to establish the reliability for dynamic measures of longitudinal arch angle (LAA) and navicular height (NH) and to examine to what extent static and dynamic measures thereof are related. Intra-rater reliability of LAA and NH measures was tested on a sample of 17 control subjects. Subsequently, 79 subjects were tested while walking on a treadmill. The ranges and minimum values for LAA and NH during ground contact were identified over 20 consecutive steps. A geometric error model was used to simulate effects of marker placement uncertainty and skin movement artifacts. Results demonstrated the highest reliability for the minimum NH (MinNH), followed by the minimum LAA (MinLAA), the dynamic range of navicular height (DeltaNH) and the range of LAA (DeltaLAA) while all measures were highly reliable. Marker location uncertainty and skin movement artifacts had the smallest effects on measures of NH. The use of an alignment device for marker placement was shown to reduce error ranges for NH measures. Therefore, DeltaNH and MinNH were recommended for functional dynamic foot characterization in the sagittal plane. There is potential for such measures to be a suitable predictor for overuse injuries while being obtainable in clinical settings. Future research needs to include such dynamic but simple foot assessments in large-scale clinical studies.

Video based analysis of dynamic midfoot function and its relationship with Foot Posture Index scores.

INTRODUCTION: Various studies have demonstrated significant as well as non-significant relationships between static evaluation of foot posture and injury likelihood. Therefore, the relationship of static and dynamic measures needs to be established as in clinical settings time consuming dynamic methods are often not feasible. PURPOSE: Assess reliability of a new method to quantify midfoot movement and validate the use of Foot Posture Index (FPI) classification as predictor of dynamic foot function during walking. METHOD: Foot type was classified using FPI in 280 randomly selected adult participants (mean age 43.4 years). A Video Sequence Analysis (VSA) system was used to quantify midfoot kinematics during walking. Navicula drop (DeltaNH) and minimal navicula height (NHL) were compared with FPI. RESULTS: The Intraclass Correlation Coefficients (ICC) for DeltaNH and NHL ranged from 0.65 to 0.95 with a coefficient of repeatability of 1.4 mm for DeltaNH and 4.5 mm for NHL. System precision was estimated at 0.99 mm for DeltaNH and 3.18 mm for NHL. DeltaNH was significantly positively correlated with FPI scores while NHL decreased with increasing FPI. However, the FPI model predicted only 13.2% of the variation in DeltaNH and 45% of the variation in NHL during walking (p<0.001). CONCLUSION: The VSA was proven as a reliable and precise method to quantify midfoot kinematics. FPI scores and individual components of the FPI show strong statistical relationships to dynamic measures but individual predictions remain questionable. Dynamic midfoot measures are recommended for clinical foot assessments.

Global gene expression analysis in fetal mouse ovaries with and without meiosis and comparison of selected genes with meiosis in the testis.

In order to identify novel genes involved in early meiosis and early ovarian development in the mouse, we used microarray technology to compare transcriptional activity in ovaries without meiotic germ cells at embryonic age 11.5 (E11.5) and E13.5 ovaries with meiosis. Overall, 182 genes were differentially expressed; 134 were known genes and 48 were functionally uncharacterized. A comparison of our data with the literature associated, for the first time, at least eight of the known genes with female meiosis/germ cell differentiation (Aldh1a1, C2pa, Tex12, Stk31, Lig3, Id4, Recql, Piwil2). These genes had previously only been described in spermatogenesis. The microarray also detected an abundance of vesicle-related genes of which four were upregulated (Syngr2, Stxbp1, Ric-8, SytIX) and one (Myo1c) was downregulated in E13.5 ovaries. Detailed analysis showed that the temporal expression of SytIX also coincided with the first meiotic wave in the pubertal testis. This is the first time that SytIX has been reported in non-neuronal tissue. Finally, we examined the expression of one of the uncharacterized genes and found it to be gonad-specific in adulthood. We named this novel transcript "Gonad-expressed transcript 1" (Get-1). In situ hybridization showed that Get-1 was expressed in meiotic germ cells in both fetal ovaries and mature testis. Get-1 is therefore a novel gene in both male and female meiosis.

Human FATE is a novel X-linked gene expressed in fetal and adult testis.

Previously, we identified a partial cDNA sequence of a novel human transcript, designated fetal and adult testis expressed transcript (FATE). FATE is testis-specific in fetal life and co-expressed with SRY in a 7 weeks old fetal testis, suggesting a function in early testicular differentiation. Herein, full-length cDNA clones of human and porcine FATE were isolated and the gene structure and promoter region of the human FATE gene was characterized. The human FATE gene, which maps to Xq28, consists of five exons spanning approximately 7 kb of genomic DNA. Examination of 1 kb of the FATE promoter region revealed the presence of a putative steroidogenic factor 1 (SF-1) binding site at position -79 to -71 upstream of the transcription start site. We propose that FATE might represent a novel target gene of SF-1 in human testicular differentiation and/or germ cell development.

Birth outcome following maternal use of fluoroquinolones.

The aim of the study was to examine fetal risk associated with intrauterine exposure to fluoroquinolones. By using on record linkage between a Prescription Database and the Birth Registry in Denmark, the offspring of 57 users of fluoroquinolones and of 17259 patients who had no prescriptive medication during pregnancy, were compared in a cohort study. Among the users, the prevalence rate ratios of congenital abnormalities, preterm birth and low birth weight were 1.30 (95% CI: 0.30-5.30),1.53 (95% CI: 0.62-3.80) and 1.17 (95% CI: 0.15-8.90), respectively. The risk of congenital abnormalities among users of fluoroquinolones during pregnancy was close to unity. Despite these limitations of statistical analysis the study suggested that the use of fluoroquinolones during pregnancy may not be a major risk factor to the foetus.

Do pregnant women report use of dispensed medications?

Surveillance of drug safety in pregnancy often draws on administrative prescription registries. Noncompliance in the use of prescribed medication may be frequent among pregnant women owing to their fear of fetotoxic side effects. To estimate compliance in the use of prescription drugs dispensed during pregnancy, we compared prescription data from the North Jutland Prescription Database with information on drug use provided by pregnant women to the Danish National Birth Cohort (DNBC), which is a health interview survey. We used the North Jutland Prescription Database to identify all prescription drugs dispensed during pregnancy for the 2,041 women who were enrolled in the DNBC in the County of North Jutland, Denmark. Compliance was defined as the probability of reporting drug use in DNBC after purchasing a dispensed prescription drug. The overall compliance to drugs purchased within 120 days before the interview was 43% (95% confidence interval = 40-46). Drugs used for treating chronic diseases, for example, beta-blockers, insulin, thyroid hormones, and diuretic and antiepileptic drugs, were always reported to be used, but compliance was low for drugs used for local or short-term treatment such as antihistamines, antibiotics, antacids, nonsteroid anti-inflammatory drugs, and gynecologic drugs. Thus, for the latter drug groups the prescription database may provide an incomplete identification of exposure. Neither data source is unbiased regarding actual drug intake. Nevertheless, our results indicate that for some drug groups risk assessment studies based on prescription data may produce false negative results as a result of noncompliance.

A population-based prescription study of asthma drugs during pregnancy: changing the intensity of asthma therapy and perinatal outcomes.

BACKGROUND: Among the goals of gestational asthma, therapy is optimisation of pulmonary function. According to the US Food and Drug Administration, no asthma drugs can be considered 'safe' during pregnancy. Fear of adverse fetal effects may thus lead to restrictive use of asthma drugs during pregnancy, and no population-based studies concerning gestational asthma therapy exist. OBJECTIVES: To examine whether asthma drugs or changing intensity of asthma therapy during pregnancy was associated with deviations from expected values of gestational age, birth weight, length at birth, or malformations. METHODS: The Birth Registry was used to identify all 15,756 primiparous women who gave birth in the County of North Jutland between 1991 and 1996. According to the North Jutland Prescription Database, 303 of these women received prescriptions for asthma drugs during pregnancy. Women who did not purchase any prescription drugs during pregnancy constituted the reference group. CONCLUSION: Women who received prescriptions for asthma drugs during pregnancy gave birth to infants with birth weight and length at birth within the expected limits. Reducing intensity of asthma treatment during pregnancy was associated with lower birth weight and length at birth. This may indicate that pregnant women chose to discontinue therapy although their disease severity justifies continuation of treatment. However, analyses did not take into account important clinical variables, and results could also be due to confounding factors or chance.

Influence of day care attendance on the use of systemic antibiotics in 0- to 2-year-old children.

OBJECTIVE: To examine the association between time spent in different public day care settings and prescription of systemic antibiotics. Design. Population-based cohort study of 5035 Danish children born in 1997 followed from birth to June 30, 1999. METHODS: The study was performed by the linkage of records drawn from administrative registries. Exposure was the total time spent in a day care home or day care center. Outcome was the first prescription of a systemic antibiotic. Possible perinatal and sociodemographic confounding factors were considered by statistical analysis. RESULTS: During the first year of life, 39.8% of the girls and 51.1% of the boys received at least 1 antibiotic prescription drug. Enrollment in a day care setting doubled a child's risk of receiving a prescription drug (adjusted relative risk in day care home 1.9, 95% confidence interval: 1.7-2.0; adjusted relative risk in day care center 2.0, 95% confidence interval: 1.7-2.3). Only age confounded the analyses. Age >1 year at the starting time in day care reduced the risk of receiving antibiotic prescriptions during the first 3 months after enrollment. CONCLUSIONS: Enrollment in public day care facilities raised the risk of receiving an antibiotic prescription drug to the same extent in day care homes as well as in day care centers, so we cannot recommend one facility over the other based on the present study. Children <1 year old at enrollment were most at risk, suggesting that extension of parental leave may reduce the use of antibiotics.