Prevalence of and risk factors for self-reported menstrual changes following COVID-19 vaccination: a Danish cohort study.

STUDY QUESTION: Are there some characteristics that render individuals more susceptible to report menstrual changes following the Coronavirus disease 2019 (COVID-19) vaccination? SUMMARY ANSWER: We found that 30% of menstruating women reported menstrual changes following COVID-19 vaccination and several potential risk factors including stress, vaccine concerns, severe COVID-19 infection, and immediate vaccine symptoms were associated with these reports. WHAT IS KNOWN ALREADY: Studies suggest that COVID-19 vaccination might temporarily prolong menstrual cycle length by less than 1 day. Specific characteristics may trigger menstrual changes in temporal relation to the vaccination simply by chance or render women more vigilant to potential menstrual changes after being vaccinated. However, research investigating potential risk factors for reporting menstrual changes following COVID-19 vaccination is limited. STUDY DESIGN, SIZE, DURATION: A population-based Danish cohort study. Data were collected from May 2021 to December 2021 as a part of the BiCoVac Cohort with the aim of examining non-specific effects following COVID-19 vaccination. The main study population included 13 648 menstruating women aged 16-65 years who completed all surveys, received their first dose of a COVID-19 vaccine during the data collection period, and completed questions related to their menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Potential risk factors included 14 biological, physical, or psychological measures. Information on most potential risk factors was self-reported and collected before the participants' first COVID-19 vaccination. Information about any menstrual change following COVID-19 vaccination was self-reported at the end of the data collection period. Logistic regression analyses were used to estimate crude and adjusted odds ratios (ORs) with 95% CIs for the association between each potential risk factor and reporting menstrual changes following COVID-19 vaccination. MAIN RESULTS AND THE ROLE OF CHANCE: Any menstrual change following COVID-19 vaccination was reported by 30% of menstruating women. Most of the potential risk factors were associated with reports of menstrual changes following COVID-19 vaccination. In particular, higher odds were found among women who reported ≥5 immediate vaccine symptoms; OR 1.67 [1.50-1.86], had had a prior severe COVID-19 infection; OR 2.17 [1.40-3.35], had a high-stress level at baseline; OR 1.67 [1.32-2.10], or were concerned about COVID-19 vaccines prior to vaccination; OR 1.92 [1.50-2.45]. Lower odds were found among women with regular menstrual cycles using hormonal contraception; OR 0.71 [0.65-0.78]. LIMITATIONS, REASONS FOR CAUTION: We were unable to address the causal effect of COVID-19 vaccination on the reported menstrual changes, as information about menstrual changes was not available among non-vaccinated women. WIDER IMPLICATIONS OF THE FINDINGS: The study identified several potential risk factors for reporting menstrual changes following COVID-19 vaccination. Further studies are needed to establish causal associations and the clinical impact of self-reported menstrual changes. STUDY FUNDING/COMPETING INTEREST(S): The BiCoVac data collection was funded by TrygFonden (id-number: 153678). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Immediate adverse reactions following COVID-19 vaccination among 16-65-year-old Danish citizens.

INTRODUCTION: There is sparse knowledge of immediate adverse reactions following COVID-19 vaccination. OBJECTIVE: This study aimed to estimate the frequency and number of immediate adverse reactions following COVID-19 vaccination in a Danish population. METHODS: The study used data from the Danish population-based cohort study BiCoVac. The frequencies of 20 self-reported adverse reactions were estimated for each vaccine dose stratified by sex, age, and vaccine type. Also, the distributions of number of adverse reactions following each dose were estimated stratified by sex, age, vaccine type, and prior COVID-19 infection. RESULTS: A total of 889,503 citizens were invited and 171,008 (19 %) vaccinated individuals were included in the analysis. The most frequently reported adverse reaction following the first dose of COVID-19 vaccine was redness and/or pain at the injection site (20 %) while following the second and third dose, tiredness was the most frequently reported adverse reaction (22 % and 14 %, respectively). Individuals aged 26-35 years, females, and those with a prior COVID-19 infection were more likely to report adverse reactions compared with older individuals, males, and those with no prior COVID-19 infection, respectively. Following the first dose, individuals vaccinated with ChAdOx1-2 (AstraZeneca) reported more adverse reactions compared with individuals vaccinated with other vaccine types. Individuals vaccinated with mRNA-1273 (Moderna) reported more adverse reactions following the second and third dose compared with individuals vaccinated with BNT162b2 (Pfizer-BioNTech). CONCLUSION: The frequency of immediate adverse reactions was highest among females and younger persons, however, most of the Danish citizens did not experience immediate adverse reactions following COVID-19 vaccination.

Evaluating the performance of the Charlson Comorbidity Index (CCI) in fracture risk prediction and developing a new Charlson Fracture Index (CFI): a register-based cohort study.

The Charlson Comorbidity Index (CCI) may be applicable for predicting fracture risk since several diagnoses from the index are predictors of fracture. Main results were that the CCI was updated to predict risk of hip fracture with fair precision and that the index could be useful in detecting high-risk individuals. PURPOSE: Several of the Charlson Comorbidity Index (CCI) diagnoses are validated predictors of fracture. The purpose of this study was to evaluate the performance of the CCI 1987 by Charlson et al. and of the CCI 2011 by Quan et al. in predicting major osteoporotic fracture (MOF) and hip fracture (HF). Furthermore, it was examined whether the index could be modified to improve fracture risk prediction. METHODS: The study population included the entire Danish population aged 45 + years as per January 1, 2018. The cohort was split randomly 50/50 into a development and a validation cohort. CCI diagnoses and fracture outcomes were identified from hospital diagnoses. The weighting of diagnoses was updated in a new Charlson Fracture Index (CFI) using multivariable logistic regression. Predictive capabilities of the CCI 1987, the updated CCI 2011 and the new Charlson Fracture index were evaluated in the validation cohort by receiver operating characteristics (ROC) curves and area under the curve (AUC). RESULTS: In the validation cohort, the 1987 and 2011 CCIs resulted in AUCs below or around 0.7 in prediction of MOF and HF in both sexes. The CFI resulted in AUCs < 0.7 in prediction of MOF in both sexes. In prediction of HF, the CFI resulted in AUC of 0.755 (95% CI 0.749; 0.761) in women and 0.782 (95% CI 0.772; 0.793) in men. CONCLUSION: The 1987 and 2011 CCIs showed overall poor accuracy in fracture risk prediction. The CFI showed fair accuracy in prediction of HF in women and in men.

Maternal rheumatoid arthritis during pregnancy and neurodevelopmental disorders in offspring: a systematic review.

Objective: To summarize the available literature on in utero exposure to maternal rheumatoid arthritis (RA) and its influence on the risk of neurodevelopmental disorders (NDDs) in offspring.Method: We conducted a systematic literature review and assessed the internal validity of studies with the Newcastle Ottawa Scale tool.Results: Six studies were included. Three reported on autism spectrum disorders; one cohort study indicated a slightly elevated risk, and two case-control studies reported too few cases for risk assessment. Two large cohort studies reported elevated hazard ratios for epilepsy in offspring, in overlapping populations. One study on attention deficit hyperactivity disorder (ADHD) reported higher odds for maternal RA during pregnancy, among children with ADHD.Conclusion:Few studies were found specifically studying maternal RA during pregnancy and NDDs in offspring. The studies pointed towards a moderately higher risk of these outcomes; however, reporting bias appears to be a problem. Additional studies of appropriate design and power are needed.

Validation of the Danish versions of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaires (BRAFs).

Objective: This study aimed to validate the Danish versions of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ) and BRAF Numerical Rating Scale version 2 (NRSv2).Method: We tested face and content validity, internal consistency, criterion validity, construct validity, and reproducibility for the BRAF-MDQ, and face and criterion validity and reproducibility for the BRAF-NRS.Results: In all, 224/236 patients (95%) completed the questionnaires [70% female, mean ± sd age 59 ± 13.04 years, disease duration 11.2 ± 9.49 years, Health Assessment Questionnaire (HAQ) 0.724 ± 0.70, and 28-joint Disease Activity Score-C-reactive protein 2.55 ± 1.24]. The unidimensionality for the physical and cognitive fatigue subscales was confirmed, whereas the living with fatigue and emotional fatigue subscales were not unidimensional. Cronbach's α was 0.94 for the BRAF-MDQ total and 0.78-0.92 for the four subscales. The correlations between BRAF-MDQ and various measures were: 36-item Short Form Health Survey (SF-36) vitality subscale, 0.75; Hospital Anxiety and Depression Scale (HADS) anxiety subscale, 0.65; HADS depression subscale, 0.62; visual analogue scale (VAS) pain, 0.62; VAS global, 0.73; and HAQ, 0.62. The intraclass correlation coefficient for agreement was 0.995. A Bland-Altman plot showed a mean ± sd difference of -1.9 ± 3.62 for BRAF-MDQ. Correlation coefficients between the BRAF-NRSv2 subscales and other subscales were: BRAF-MDQ subscales, 0.57-0.93; SF-36 vitality subscale, 0.54-0.68; and VAS fatigue, 0.66-0.82.Conclusions: The Danish BRAFs are considered valid and reliable for use among Danish patients with rheumatoid arthritis, despite the subscales living with fatigue and emotional fatigue not being unidimensional, as they are in the original version.

General medical conditions and mortality in women with postpartum psychiatric disorders.

BACKGROUND: Psychiatric patients have an increased risk of general medical conditions and mortality, but no study has systematically explored these outcomes among women with mental disorders following childbirth (postpartum psychiatric disorders: PPD). Therefore, we aimed to investigate the risk of subsequent general medical conditions and mortality in women with a broad spectrum of PPD. METHODS: This register-based cohort study followed all Danish women born after January 1, 1960, until January 1, 2016. The exposure of interest was (i) mild-moderate PPD: first-ever prescription of psychotropic medication (ATC codes: N03-N07) and (ii) severe PPD: first-ever in- or out-patient contact to a psychiatric facility, both within six months postpartum. Outcomes of interest were (i) hospital-registered chronic medical conditions and (ii) mortality from natural and unnatural causes. We included 1 841 949 women representing 22 615 310 person-years at risk. RESULTS: Among 15 852 women with mild-moderate PPD and 4266 women with severe PPD, we found a higher risk of any subsequent general medical condition (mild-moderate PPD: IRR 1.25; 95% CI 1.20-1.31 and severe PPD: IRR 1.35; 95% CI: 1.24-1.48) when compared to the female background population. Mortality from both natural and unnatural causes was higher in both groups: Mild-moderate PPD: natural causes MRR 1.37; 95% CI: 1.17-1.61; unnatural causes MRR 1.52; 95% CI: 1.10-2.11, and severe PPD: natural causes MRR 1.42; 95% CI 1.02-2.00, and unnatural causes MRR 5.05; 95% CI: 3.40-7.51. CONCLUSIONS: This first overview of general medical prognosis in PPD shows that women at either end of the spectrum are at increased risk of subsequent chronic medical conditions and overall mortality.

Birth weight for gestational age and the risk of infertility: a Danish cohort study.

STUDY QUESTION: Is birth weight for gestational age associated with infertility in adulthood among men and women? SUMMARY ANSWER: Being born small for gestational age (SGA) was associated with infertility in adulthood among men. WHAT IS KNOWN ALREADY: Fetal growth restriction may affect fertility, but results from previous studies have been inconsistent. STUDY DESIGN, SIZE, DURATION: In this population-based cohort study, we used data from a Danish birth cohort, including 5594 men and 5342 women born between 1984 and 1987. Information on infertility was obtained from Danish health registers during the period from the participants' 18th birthday and up until 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were men and women born in two Danish municipalities, Aalborg and Odense. Information on birth weight and gestational age was obtained from birth records, and information on infertility diagnoses and fertility treatment was retrieved from the Danish National Patient Registry (NPR) and the Danish In Vitro Fertilisation (IVF) registry. Information on potential maternal confounders was obtained from questionnaires during pregnancy and was included in adjusted analyses. Logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for infertility according to birth weight for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: Men born SGA had a 55% higher risk of being diagnosed with or treated for infertility compared to men born appropriate for gestational age (AGA) (adjusted OR = 1.55, 95% CI: 1.09-2.21). The association attenuated after exclusion of men born with hypospadias or cryptorchidism (OR = 1.37, 95% CI: 0.93-2.01). No association was found between women's birth weight for gestational age and risk of infertility (adjusted OR = 1.00, 95% CI: 0.73-1.37). LIMITATIONS, REASONS FOR CAUTION: Estimation of gestational age is associated with some uncertainty and might have caused non-differential misclassification. The study design implicitly assumed similar distribution of reproductive and health-seeking behaviour across the groups that were compared. WIDER IMPLICATIONS OF THE FINDINGS: Men born SGA had a higher risk of infertility. Genital malformations may account for part of the observed association, but this must be explored further. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Health, Aarhus University. No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Reproductive life in women with celiac disease; a nationwide, population-based matched cohort study.

STUDY QUESTION: How does celiac disease (CD) influence women's reproductive life, both prior to and after the diagnosis? SUMMARY ANSWER: Prior to the diagnosis of CD, an increased risk of adverse pregnancy outcomes was seen, whereas after the diagnosis, no influence on reproductive outcomes was found. WHAT IS KNOWN ALREADY: CD has been associated with several conditions influencing female reproduction and pregnancy outcomes including spontaneous abortion and stillbirth. STUDY DESIGN, SIZE, DURATION: A nationwide matched cohort study following 6319 women diagnosed with CD and 63166 comparison women and identifying reproductive events between the ages of 15 and 50 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Through linkage of several Danish national health registers, we identified all women diagnosed with CD between 1977 and 2016. We identified an age- and sex-matched comparison cohort and obtained data on reproductive outcomes for both cohorts. Adjusted stratified Cox and logistic regression models were used to estimate differences in reproductive outcomes between women with and without CD. MAIN RESULTS AND THE ROLE OF CHANCE: Comparing women with diagnosed CD with the non-CD women, the chance of pregnancy, live birth and risk of stillbirth, molar and ectopic pregnancy, spontaneous abortion and abortion due to foetal disease was the same. However, prior to being diagnosed, CD women had an excess risk of spontaneous abortion equal to 11 extra spontaneous abortions per 1000 pregnancies (adjusted odds ratio (OR) = 1.12, 95% CI: 1.03, 1.22) and 1.62 extra stillbirths per 1000 pregnancies (adjusted OR = 1.57, 95% CI: 1.05, 2.33) compared with the non-CD women. In the period 0-2 years prior to diagnosis fewer pregnancies occurred in the undiagnosed CD group, equal to 25 (95% CI: 20-31) fewer pregnancies per 1000 pregnancies compared to the non-CD group and in addition, fewer undiagnosed CD women initiated ART-treatment in this period, corresponding to 4.8 (95% CI: 0.9, 8.7) fewer per 1000 women compared to non-CD women. LIMITATIONS, REASONS FOR CAUTION: Validity of the diagnoses in the registers was not confirmed, but reporting to the registers is mandatory for all hospitals in Denmark. Not all spontaneous abortions will come to attention and be registered, whereas live- and stillbirths, ectopic and molar pregnancies and abortion due to foetal disease are unlikely not to be registered. We adjusted for several confounding factors but residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that undiagnosed CD can affect female reproduction and the focus should be on early detection of CD in risk groups. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health Research Fund of Central Denmark Region and The Hede Nielsens Foundation, Denmark. The authors report no conflicts of interest in this work.

Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.

BACKGROUND: Birth by Cesarean section (C-section) may increase the risk for non-communicable diseases. We aimed to examine the relation of birth by C-section with offspring overweight and markers of cardiometabolic risk in a prospective observational cohort with 20 years of follow-up. METHODS: The Danish Fetal Origins Cohort enrolled 965 pregnant women in 1988-1989. In 2008, a follow-up study of the offspring was completed. The offspring were invited to participate in a clinical examination with measurements of anthropometry and a fasting blood sample (n=443). In addition, 252 offspring completed a self-administered questionnaire with questions on height and weight, leaving us with a study sample of 695 offspring. Offspring overweight at 20 years was defined as body mass index (BMI)⩾25 kg m-2. We also analyzed blood pressure and fasting blood samples for cardiometabolic risk factors including insulin, leptin and adiponectin, and lipid concentrations. RESULTS: In the cohort, 7% were born by C-section, and at age 20 years, 18% of the offspring had a BMI ⩾25 kg m-2. Birth by C-section was associated with increased odds of overweight or obesity at 20 years (Odds ratio=2.17 (95% confidence interval (CI): 1.10, 4.27)) after adjustment for potential confounders. Birth by C-section was also associated with higher serum concentrations of total cholesterol (8.5%, 95% CI: 1.1-16.5), low-density lipoprotein cholesterol (12.6%, 95% CI: 1.0, 25.5), leptin (73.1%, 95% CI: 5.9, 183.1) and Apolipoprotein B (0.08 g l-1, 95% CI: 0.04, 0.15). In contrast, birth by C-section was not related to blood pressure or serum concentrations of insulin, adiponectin, triglycerides, high-density lipoprotein or Apolipoprotein A. CONCLUSION: Birth by C-section was associated with higher frequency of dysmetabolic traits in offspring independently of shared risk factors. Further research aimed at replicating these findings and elucidating the underlying biological mechanisms of this relation is needed.

The effect of CT scanners in the trauma room - an observational study.

BACKGROUND: A CT scanner incorporated in the trauma resuscitation bay may benefit trauma patients by fastening work-up times; however, evidence in the area is still sparse. We assessed if time from admission to first CT scan was lower after incorporation of a CT scanner in the resuscitation bay. METHODS: We included trauma patients admitted in two 1-year periods, before and after a major rebuilding of the trauma room. Beforehand, one CT scanner was located in an adjacent room. After the rebuilding, two mobile CT scanners were placed in the resuscitation bays, where a moving gantry was combined with a trauma resuscitation table. Subgroup analyses were performed on severely injured and patients with traumatic brain injury. RESULTS: We included 784 patients before and 742 patients after the reconstruction. Case-mix differed between study periods as there was a higher proportion of severe injuries, traumatic brain injury and penetrating trauma in the after period. We found a minor increase in time to CT in the after period (20 vs. 21 min, P = 0.008). In a multivariate regression analysis adjusted for differences in case-mix and with time to CT as outcome, period was an insignificant explanatory variable [ß (before vs. after): 0.96 min 95% CI: 0.9-1.02, P = 0.3]. In both subgroups, we found no significant difference in time to CT. CONCLUSION: We found no reduction in time to CT scan, when comparing a period with mobile CT scanners incorporated in the resuscitation bay to an earlier period with a CT scanner next to the trauma room.

Assessment of Competence in EVAR Procedures: A Novel Rating Scale Developed by the Delphi Technique.

OBJECTIVE/BACKGROUND: To develop a procedure specific global rating scale for assessment of operator competence in endovascular aortic repair (EVAR). METHODS: A Delphi approach was used to achieve expert consensus. A panel of 32 international experts (median 300 EVAR procedures, range 200-3000) from vascular surgery (n = 21) and radiology (n = 11) was established. The first Delphi round was based on a review of endovascular skills assessment papers, stent graft instructions for use, and structured interviews. It led to a primary pool of 83 items that were formulated as global rating scale items with tentative anchors. Iterative Delphi rounds were executed. The panellists rated the importance of each item on a 5 point Likert scale. Consensus was defined as 80% of the panel rating an item 4 or 5 in the primary round and 90% in subsequent rounds. Consensus on the final assessment tool was defined as Cronbach's alpha > .8 after a minimum of three rounds. RESULTS: Thirty-two of 35 invited experts participated. Three rounds of surveys were completed with a completion rate of 100% in the first two rounds and 91% in round three. The 83 primary assessment items were supplemented with five items suggested by the panel and reduced to seven pivotal assessment items that reached consensus, Cronbach's alpha = 0.82. The seven item rating scale covers key elements of competence in EVAR stent placement and deployment. Each item has well defined grades with explicit anchors at unacceptable, acceptable, and superior performance on a 5 point Likert scale. CONCLUSION: The Delphi methodology allowed for international consensus on a new procedure specific global rating scale for assessment of competence in EVAR. The resulting scale, EndoVascular Aortic Repair Assessment of Technical Expertise (EVARATE), represents key elements in the procedure. EVARATE constitutes an assessment tool for providing structured feedback to endovascular operators in training.

Assessment of Competence in EVAR Stent Graft Sizing and Selection.

OBJECTIVES AND BACKGROUND: The aims of this study were to develop a test of competence in endovascular aortic repair (EVAR) stent graft sizing and selection; to examine the test for evidence of validity; and to explore the experience required for the task. METHODS: The test was developed based on a literature review resulting in 22 anatomical assessment points and a graft selection. Validity evidence was explored in an international cross sectional study. Twenty-two consultants with varying levels of experience in the field (novices, intermediates, and experts) were presented with computed tomography angiography of the aortic vessels from three patients. Test scores were based on summed z-scores using the anatomical measurements and graft choices of the experts as a reference. A proficiency score was established using the contrasting groups standard setting method. RESULTS: The assessment was shown to be reliable with an intraclass correlation coefficient of 0.83 (p<.001) and high internal consistency with a Cronbach's α of .91 (p<.001). Mann-Whitney U test showed that experts performed significantly better than novices and intermediates (p<.002 and p<.005, respectively). Regarding anatomical measurements, Mann-Whitney U test could discriminate between experts and novices (p=.002), between experts and intermediates (p=.010), and between novices and intermediates (p=.036). In stent selection the experts performed significantly better than both the novices and the intermediates (p=.002 and p=.007, respectively), while there was no significant difference between the two non-expert groups (p=1). A credible passing standard with appropriate consequences was established using the contrasting groups methods. CONCLUSION: This study presents a standardised and objective assessment tool of competence in vessel analysis and stent graft selection for endovascular aortic repair. This was supported by strong validity evidence with good internal consistency and discriminatory ability. The tool may be used to facilitate training and certification of future endovascular specialists.

Prenatal antidepressant exposure and child behavioural outcomes at 7 years of age: a study within the Danish National Birth Cohort.

OBJECTIVE: To investigate the impact of prenatal antidepressant exposure on behavioural problems in children at 7 years of age. DESIGN: Nationwide population-based study. SETTING: Danish National Birth Cohort. POPULATION: A cohort of 49 178 pregnant women recruited between 1996 and 2002. METHODS: Data obtained from computer-assisted telephone interviews twice during pregnancy were used to identify children born to: (i) depressed women who took antidepressants during pregnancy (n = 210); (ii) depressed women who did not take any antidepressants during pregnancy (n = 231); and (iii) healthy women who were not depressed (n = 48 737). Childhood behavioural problems at 7 years of age were examined using the validated Danish parent-report version of the Strengths and Difficulties Questionnaire (SDQ). MAIN OUTCOME MEASURES: SDQ scores. RESULTS: No associations were observed between prenatal antidepressant exposure and abnormal SDQ scores for overall problem behaviour (adjusted relative risk, aRR 1.00; 95% confidence interval, 95% CI 0.49-2.05), hyperactivity/inattention (aRR 0.99; 95% CI 0.56-1.75), or peer problems (aRR 1.04; 95% CI 0.57-1.91). Although prenatal antidepressant exposure appeared to be associated with abnormal SDQ scores on the subscales of emotional symptoms (aRR 1.68; 95% CI 1.18-2.38) and conduct problems (aRR 1.58; 95% CI 1.03-2.42), these associations were significantly attenuated following adjustment for antenatal mood status (aRR 1.20; 95% CI 0.85-1.70 and aRR 1.19; 95% CI 0.77 1.83, respectively). Untreated prenatal depression was associated with an increased risk of all behavioural outcomes evaluated, compared with unexposed children, with significant attenuation following adjustment for antenatal mood status. CONCLUSIONS: The results of this study suggest that independent of maternal illness, prenatal antidepressant exposure is not associated with an increased risk of behavioural problems in children at 7 years of age. TWEETABLE ABSTRACT: Prenatal antidepressant exposure is not associated with an increased risk of child behavioural problems.

Prenatal exposure to persistent organic pollutants and offspring allergic sensitization and lung function at 20 years of age.

BACKGROUND: Prenatal exposures to persistent organic pollutants (POPs) have been associated with asthma medication use and self-reported symptoms, but associations with lung function and allergic sensitization have been minimally explored. The aim of the study was to examine the associations between prenatal exposures to POPs and allergic sensitization and lung function in 20-year-old offspring. METHODS: In a Danish cohort of 965 pregnant women established in 1988-1989, six polychlorinated biphenyl (PCB) congeners, hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p'-DDE) were quantified in archived maternal serum drawn in gestational week 30 (n = 872). Among those with available maternal exposure information, at age 20, 421 offspring attended attended a clinical examination including measurements of allergic sensitization (serum-specific IgE ≥ 0.35 kUA /L) (n = 418) and lung function [forced expiratory volume in one second (FEV1 ) and forced vital capacity (FVC)] (n = 414). RESULTS: There were no associations between maternal concentrations of POPs and offspring allergic sensitization at 20 years of age. Maternal concentrations of POPs were, however, positively associated with offspring airway obstruction (FEV1 /FVC < 75%). Compared to offspring in the first tertile of exposure, offspring in the third tertile of dioxin-like PCB exposure had an OR of 2.96 (95% CI: 1.14-7.70). Similar associations for non-dioxin-like PCBs, HCB, and p,p'-DDE were 2.68 (1.06-6.81), 2.63 (1.07, 6.46), and 2.87 (1.09, 7.57), respectively. No associations were observed with reduced lung function (FEV1 % of predicted value < 90%). CONCLUSION AND CLINICAL RELEVANCE: Our data indicate that prenatal exposure to POPs appears to be associated with airway obstruction but not allergic sensitization at 20 years of age. The findings support that chronic obstructive lung diseases may have at least part of their origins in early life.

First trimester coffee and tea intake and risk of gestational diabetes mellitus: a study within a national birth cohort.

OBJECTIVE: Coffee and tea consumption is associated with a decreased type 2 diabetes risk in non-pregnant adults. We examined the relation between first trimester coffee and tea consumption and gestational diabetes mellitus (GDM) risk. DESIGN: Population-based cohort study. SETTING: Denmark 1996-2002. POPULATION: Non-diabetic women with singleton pregnancies in the Danish National Birth Cohort (n = 71,239). METHODS: Estimated adjusted relative risks (RR) and 95% confidence intervals (95%CI) for the association between first trimester coffee and tea or estimated total caffeine and GDM. MAIN OUTCOME MEASURES: GDM ascertained from the National Hospital Discharge Register or maternal interview. RESULTS: Coffee or tea intake was reported in 81.2% (n = 57,882) and 1.3% (n = 912) of pregnancies were complicated by GDM. Among non-consumers, 1.5% of pregnancies were complicated by GDM. Among coffee drinkers, GDM was highest among women who drank ≥8 cups/day (1.8%) with no significant difference across intake levels (P = 0.10). Among tea drinkers, there was no difference in GDM across intake levels (1.2%; P = 0.98). After adjustment for age, socio-occupational status, parity, pre-pregnancy body mass index, smoking, and cola, there was suggestion of a protective, but non-significant association with increasing coffee (RR ≥8 versus 0 cups/day = 0.89 [95%CI 0.64-1.25]) and tea (RR ≥8 versus 0 cups/day = 0.77 [95%CI 0.55-1.08]). Results were similar by smoking status, except a non-significant 1.45-fold increased risk with ≥8 coffee cups/day for non-smokers. There was a non-significant reduced GDM risk with increasing total caffeine. CONCLUSIONS: Our results suggest that moderate first trimester coffee and tea intake were not associated with GDM increased risk and possibly may have a protective effect.

Gestational weight gain in normal weight women and offspring cardio-metabolic risk factors at 20 years of age.

OBJECTIVE: Limited knowledge exists on the long-term implications of maternal gestational weight gain (GWG) on offspring health. Our objective was to examine whether high GWG in normal weight women is associated with adult offspring cardio-metabolic risk factors. METHODS: We used a cohort of 308 Danish women who gave birth in 1988-89 and whose offspring participated in a clinical examination at 20 years of age. Main outcome measures were offspring body mass index (BMI), waist circumference, weight-regulating hormones, blood lipids and glucose metabolism. Associations were assessed using multivariable linear and logistic regression models. RESULTS: A weak positive association was observed between GWG during the first 30 weeks and offspring anthropometry. Each 1-kg increase in maternal GWG was associated with 0.1-kg m(-2) higher (95% confidence interval (CI): 0.01, 0.2) offspring BMI and 10% (95% CI: 0.1%, 20%) higher odds of offspring overweight at the age of 20 years, with similar associations observed in both sexes. However, sex differences were observed for the association between maternal GWG and specific cardio-metabolic risk factors. Hence, a 1-kg increase in GWG was associated with 3.4% (95% CI; 0.8, 6.0%) higher homeostasis model assessment-estimated insulin resistance (HOMA-IR), 3.7% (95% CI: 1.4%, 6.2%) higher insulin and 10.7% (95% CI: 5.7%, 15.9%) higher leptin levels in male offspring. These associations were not observed in females, which may partly be explained by more frequent reports of dieting and physical exercise at follow-up among female offspring. CONCLUSIONS: In normal-weight women, high GWG may have modest long-term implications on offspring cardio-metabolic risk factors at adult age.

Preschool behavioral problems in children prenatally exposed to antiepileptic drugs - a follow-up study.

We studied the association between maternal epilepsy, antiepileptic drug (AED) treatment, and behavioral problems in preschool children. In the Danish National Birth Cohort, we identified 4- to 5-year-old children whose mothers had epilepsy and received AED treatment (n=133) or not (n=304) during pregnancy and compared them with randomly selected children whose mothers did not have epilepsy (n=1193). The children's behavioral problems were assessed by the use of the Strengths and Difficulties Questionnaire (SDQ). Children prenatally exposed to AEDs more often had an abnormal total SDQ score as compared with children of women without epilepsy (odds ratio (OR)=4.8 (95% CI: 1.9-12.1)) and as compared with children of women with epilepsy who were not treated with AEDs during their pregnancy (OR=4.0 (95% CI: 1.3-12.8)). In conclusion, prenatal AED exposure may increase the risk of behavioral problems in preschool children even after adjustments for potential confounders and maternal epilepsy.

Maternal milk consumption, birth size and adult height of offspring: a prospective cohort study with 20 years of follow-up.

BACKGROUND/OBJECTIVES: Previous studies have suggested that milk consumption during pregnancy may have growth-promoting effects on the offspring in utero. Whether this effect tracks beyond the prenatal period remains unclear. We examined whether milk consumption during pregnancy is associated with infant size at birth and offspring's height- and growth-related biomarkers at ∼20 years of age. SUBJECT/METHODS: A prospective cohort of 809 Danish pregnant women was recruited in 1988-1989, with offspring follow-up at ∼20 years of age (n=685). Milk consumption was assessed at gestational week 30 using a food frequency questionnaire. Birth weight and birth length were measured according to standard procedures at delivery and converted to specific z-scores, adjusted for gestational age and gender. RESULTS: In adjusted models, maternal milk consumption of ≥150 ml/day vs <150 ml/day was associated with 0.32 higher z-scores for birth weight (95% confidence interval (CI) 0.06; 0.58) and 0.34 higher z-scores for birth length (95% CI 0.04; 0.64). At follow up, ∼20 years later, those offspring whose mothers had consumed < 150 ml milk/day tended to have 0.19 higher z-scores for height (P=0.16), ∼8% higher levels of insulin-like growth factor I (P=0.12) and ∼14% higher insulin levels (P=0.11) compared with offspring whose mothers consumed <150 ml milk/day. CONCLUSIONS: Our findings add to recent observations that maternal milk consumption may have a growth-promoting effect with respect to weight and length at birth. Furthermore, the results provide some suggestion that this effect may even track into early adult age, although further studies with more statistical power are needed for that purpose.

Maternal bereavement in the antenatal period and oral cleft in the offspring.

STUDY QUESTION: Is maternal bereavement (emotional stress) due to loss of a close relative in the antenatal period associated with the risk of oral cleft in the offspring? SUMMARY ANSWER: Our study suggests prenatal maternal bereavement is associated with an increased risk of oral cleft in the offspring, especially when the bereavement was due to a sudden death or death of a child. WHAT IS KNOWN ALREADY: The aetiology of oral cleft is unknown but includes both genetic and environmental causes. STUDY DESIGN, SIZE AND DURATION: We performed a population-based cohort study based on several national registers in Denmark from 1978 to 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our final study population consisted of 1 771 663 children. Of these 35 118 (2%) were born to mothers who experienced bereavement in the exposure window from 1 year before pregnancy to the end of the first trimester. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 3043 children were diagnosed with a cleft; 968 with cleft lip, 1206 with cleft lip and palate and 869 with a cleft palate. For overall bereavement the prevalence was 1.7 per 1 000 live born in the unexposed children and 2.2 per 1 000 live born in the exposed children. Overall, maternal bereavement due to the death of a close relative from 1 year before conception to the end of the first trimester was associated with a significantly increased risk of oral cleft [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.01; 1.61). When mothers lost a relative due to a sudden death, the risk of oral cleft in the offspring was higher (OR: 1.76, 95% CI: 1.06; 2.94). Losing a relative in the time period before pregnancy and during the first trimester showed a tendency to an increased risk. The risk increase was 77% when the mother was bereaved due to sudden death and the estimation was robust in different analytical strategies. LIMITATIONS, REASONS FOR CAUTION: It is a limitation that we only studied live born children, but most children with isolated oral cleft would survive their pregnancy and birth. Since oral cleft are rare and despite the large study population, we still had a relatively small number of cases, which results in limited power to detect small differences. We did not have actual measurements of the maternal cortisol concentration, but we believe that bereavement due to death of a close relative produces a strong stress reaction in most people. Also we did not have the opportunity to adjust for intake of folic acid and use of anti-depressant; however, analysis in a subset of the data showed no difference in these intakes between exposed and unexposed mothers. WIDER IMPLICATIONS OF THE FINDINGS: With this study we add a large-scale human cohort study to the body of literature on stress and birth defects. Our study is in agreement with previously published results and can be generalized to similar populations like the native Danish population. Severe stress may be added to the list of potential causes for oral cleft.