Cohort profile: The Copenhagen Analgesic Study-The COPANA cohort.

BACKGROUND: Development of the gonads during fetal life is complex and vital for adult reproductive health. Cell and animal studies have shown an alarming effect of mild analgesics on germ cells in both males and females. More than 50% of pregnant women use mild analgesics during pregnancy, which potentially could compromise the reproductive health of the next generation. OBJECTIVES: We present a research protocol designed to evaluate the effect of prenatal exposure to mild analgesics and endocrine-disrupting chemicals on gonadal function in the offspring. POPULATION: Healthy, singleton pregnant women and their partners. DESIGN: The COPANA cohort is a prospective, observational pregnancy and birth cohort. METHODS: Participants were enrolled during the first trimester of pregnancy. Information on the use of mild analgesics was collected retrospectively 3 months prior to pregnancy and prospectively every 2 weeks throughout the study. We collected extensive data on lifestyle and reproductive health. Biospecimens were collected in the first trimester (maternal and paternal urine- and blood samples), in the third trimester in conjunction with a study-specific ultrasound scan (maternal urine sample), and approximately 3 months post-partum during the infant minipuberty period (maternal and infant urine- and blood samples). A comprehensive evaluation of reproductive function in the infants during the minipuberty phase was performed, including an ultrasound scan of the testis or ovaries and uterus. PRELIMINARY RESULTS: In total, 685 pregnant women and their partners were included between March 2020 and January 2022. A total of 589 infants (287 males) and their parents completed the follow-up during the minipuberty phase (December 2020-November 2022). CONCLUSIONS: The Copenhagen Analgesic Study holds the potential to provide novel and comprehensive insights into the impact of early and late prenatal exposure to mild analgesics and other endocrine-disrupting chemicals on future reproductive function in the offspring.

Maternal inflammatory, lipid and metabolic markers and associations with birth and breastfeeding outcomes.

Background: Conditions in utero influence intrauterine and postnatal infant growth and a few studies indicate that maternal inflammation and insulin resistance might affect birth and breastfeeding outcomes. Furthermore, hormones in human milk (HM) may influence infant appetite-regulation and thereby milk intake, but the associations are less understood. Objective: (1) To investigate associations between maternal inflammatory, lipid and metabolic markers and birth and breastfeeding outcomes, and (2) to assess predictors of maternal inflammatory, lipid and metabolic markers in pregnancy. Methods: Seventy-one mother-infant dyads participating in the Mothers, Infants and Lactation Quality (MILQ) study were included in the present study. Fasting blood samples were collected around 28th gestational week, and HM samples at three time points from 1.0 to 8.5 months, where milk intake was assessed using 24-h test weighing. Maternal plasma inflammatory, lipid and metabolic markers included high-sensitive C-reactive protein (hs-CRP), tumor-necrosis factor-α (TNFα), interferon-γ (IFNγ), Interleukin (IL)-6, IL-8, high-, low-, and very-low-density lipoprotein (HDL, LDL, VLDL), total-cholesterol, triglycerides, leptin, adiponectin, insulin, C-peptide, the homeostasis model assessment of insulin resistance (HOMA-IR) and glucose concentration at t = 120 min following an oral glucose tolerance test. Of these, TNFα, IFNγ, IL-6, IL-8, leptin, adiponectin and insulin were also measured in HM samples. Results: HDL in pregnancy was inversely associated with gestational age (GA) at birth and GA-adjusted birthweight z-score, whereas triglycerides and glucose (t = 120) were positively associated with GA-adjusted birthweight z-score. Higher hs-CRP, VLDL and triglycerides were associated with a higher placental weight. Furthermore, higher HDL, insulin, leptin and HOMA-IR were associated with longer duration of exclusive breastfeeding (EBF). Higher pre-pregnancy BMI was the main predictor of higher levels of hs-CRP, log-TNFα, leptin, insulin, C-peptide, and HOMA-IR. Conclusion: Maternal lipid and metabolic markers influenced birthweight z-score and placental weight as well as duration of EBF. Furthermore, pre-pregnancy BMI and maternal age predicted levels of several inflammatory and metabolic markers during pregnancy. Our findings indicate that maternal lipid and metabolic profiles in pregnancy may influence fetal growth and breastfeeding, possibly explained by overweight and/or higher placental weight. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT03254329.

Paracetamol use prior to and in early pregnancy: Prevalence and patterns among women with and without chronic medical diseases.

AIMS: Paracetamol is commonly consumed by pregnant women, even though recent data have questioned its safety. Having chronic medical diseases (CMDs) may influence the prevalence of use during pregnancy. We aimed to assess the prevalence and patterns of use 3 months prior to pregnancy and in the first trimester among women with and without CMDs and the potential influence of CMDs on frequent use in the first trimester. METHODS: We used patient-reported data from the Copenhagen Pregnancy Cohort from 1 October 2013 to 23 May 2019 with information on CMDs and paracetamol use. Prevalence and patterns of use were assessed descriptively and by multivariable logistic regression models. RESULTS: We included 24 019 pregnancies. Use of paracetamol prior to and in early pregnancy was significantly higher among women with CMDs compared to women without (40.7% vs. 35.8% and 9.1% vs. 5.1%, respectively). Women with CMDs were 2.7 times more likely to have a frequent intake compared to women without [aOR 2.69 (95% CI 2.05-3.32)]. Migraine, rheumatoid arthritis and mental disease were associated with a higher use of paracetamol [aOR 4.39 (3.20-6.02), aOR 4.32 (2.41-7.72) and aOR 2.74 (1.67-4.49), respectively]. CONCLUSIONS: Women with CMDs had a higher paracetamol use before and during pregnancy than women without CMDs. Women with migraine, rheumatoid arthritis and mental disease showed the highest risk of frequent use. This study highlights the importance of discussing pain relief in pregnancy and evaluating the influence of maternal CMDs when assessing adverse effects of paracetamol use during pregnancy.

A group B Streptococcus alpha-like protein subunit vaccine induces functionally active antibodies in humans targeting homotypic and heterotypic strains.

Maternal vaccination is a promising strategy for preventing neonatal disease caused by group B Streptococcus. The safety and immunogenicity of the prototype vaccine GBS-NN, a fusion protein consisting of the N-terminal domains of the alpha-like proteins (Alp) αC and Rib, were recently evaluated favorably in healthy adult women in a phase 1 trial. Here we demonstrate robust immunoglobulin G (IgG) and immunoglobulin A (IgA) responses against αC and Rib, as well as against the heterotypic Alp family members Alp1-Alp3. IgA and heterotypic IgG responses are more variable between subjects and correlate with pre-existing immunity. Vaccine-induced IgG mediates opsonophagocytic killing and prevents bacterial invasion of epithelial cells. Like the vaccine-induced response, naturally acquired IgG against the vaccine domains is dominated by IgG1. Consistent with the high IgG1 cross-placental transfer rate, naturally acquired IgG against both domains reaches higher concentrations in neonatal than maternal blood, as assessed in a separate group of non-vaccinated pregnant women and their babies.

Pregnancy outcomes in relation to disease activity and anti-rheumatic treatment strategies in women with rheumatoid arthritis: a matched cohort study from Sweden and Denmark.

OBJECTIVES: To explore the association of maternal RA to pregnancy outcomes, especially preterm birth (PTB) and small for gestational age (SGA), in relation to disease activity and anti-rheumatic treatment before and during pregnancy. METHODS: By linking prospective clinical rheumatology registers (CRR) in Sweden (the Swedish Rheumatology Quality Register, SRQ) and Denmark (the Danish clinical quality register, DANBIO) with medical birth registers, we identified 1739 RA-pregnancies and 17 390 control-pregnancies (matched 1:10 on maternal age, birth year, parity) with delivery 2006-18. Disease activity (DAS28, CRP, HAQ score) and anti-rheumatic treatment 9 months before and during pregnancy were identified through CRR and prescribed drug registers. Using logistic regression, we estimated adjusted odds ratios (aOR) with 95% CI for PTB and SGA overall and stratified by disease activity and anti-rheumatic treatment before and during pregnancy, adjusting for maternal characteristics. RESULTS: We found increased aOR of PTB [1.92 (1.56-2.35)] and SGA [1.93 (1.45-2.57)] in RA-pregnancies vs control-pregnancies. For RA-pregnancies with DAS28-CRP ≥4.1 vs <3.2 during pregnancy, aOR was 3.38 (1.52-7.55) for PTB and 3.90 (1.46-10.4) for SGA. Use of oral CS (yes/no) during pregnancy resulted in an aOR of 2.11 (0.94-4.74) for PTB. The corresponding figure for biologics was 1.38 (0.66-2.89). Combination therapy, including biologics before pregnancy, was a marker of increased risk of both PTB and SGA. CONCLUSION: During pregnancy, disease activity rather than treatment seems to be the most important risk factor for PTB and SGA in RA. Women with RA should be carefully monitored during pregnancy, especially if they have moderate to high disease activity or/and are treated with extensive anti-rheumatic treatment.

How often will midwives and obstetricians experience obstetric emergencies or high-risk deliveries: a national cross-sectional study.

OBJECTIVE: To estimate how often midwives, specialty trainees and doctors specialised in obstetrics and gynaecology are attending to specific obstetric emergencies or high-risk deliveries (obstetric events). DESIGN: A national cross-sectional study. SETTING: All hospital labour wards in Denmark. PARTICIPANTS: Midwives (n=1303), specialty trainees (n=179) and doctors specialised in obstetrics and gynaecology (n=343) working in hospital labour wards (n=21) in Denmark in 2018. METHODS: Categories of obstetric events comprised of Apgar score <7/5 min, eclampsia, emergency caesarean sections, severe postpartum haemorrhage, shoulder dystocia, umbilical cord prolapse, vaginal breech deliveries, vaginal twin deliveries and vacuum extraction. Data on number of healthcare professionals were obtained through the Danish maternity wards, the Danish Health Authority and the Danish Society of Obstetricians and Gynaecologists. We calculated the time interval between attending each obstetric event by dividing the number of events occurred with the number of healthcare professionals. OUTCOME MEASURES: The time interval between attending a specific obstetric event. RESULTS: The average time between experiencing obstetric events ranged from days to years. Emergency caesarean sections, which occur relatively frequent, were attended on average every other month by midwives, every 9 days for specialty trainees and every 17 days by specialist doctors. On average, rare events like eclampsia were experienced by midwives only every 42 years, every 6 years by specialty trainees and every 11 years by specialist doctors. CONCLUSIONS: Some obstetric events occur extremely rarely, hindering the ability to obtain and maintain the clinical skills to manage them through clinical practice alone. By assessing the frequency of a healthcare professionals attending an obstetric emergency, our study contributes to assessing the need for supplementary educational initiatives and interventions to learn and maintain clinical skills.

Lifestyle Habits among Pregnant Women in Denmark during the First COVID-19 Lockdown Compared with a Historical Period-A Hospital-Based Cross-Sectional Study.

The first national lockdown in Denmark due to the COVID-19 pandemic was declared on 11 March 2020. From this date, national restrictions were imposed. We aimed to assess the potential influence of this first nationwide lockdown on exercise, alcohol consumption, and smoking in early pregnancy. Using a cross-sectional study based on routinely collected patient-reported data, we compared the lifestyle habits of women who were pregnant during the first phase of the pandemic (COVID-19 group) (n = 685) with those of women who were pregnant the year before (Historical group) (n = 787). We found a reduction in any exercise (PR = 0.91, 95% CI (0.84 to 0.99), in adherence to national recommendations of exercise (PR = 0.89, 95% CI (0.80 to 0.99), in cycling (15% vs. 28%, p < 0.0001), and swimming (0.3% vs. 3%, p = 0.0002) in the COVID-19 group compared with the Historical group. The prevalence of binge drinking was reduced in the COVID-19 group compared with the Historical group (PR = 0.80, 95% CI (0.68 to 0.93). In contrast, the prevalence of any weekly alcohol consumption and smoking cessation during pregnancy was similar between groups. Our findings indicate that national restrictions due to the COVID-19 pandemic influenced the lifestyle habits of pregnant women and should be addressed in antenatal counseling.

Worries among pregnant Danish women with chronic medical conditions - A cross sectional study with data from the Copenhagen pregnancy cohort.

OBJECTIVE: Pregnancy is a time of uncertainty and worries are common. Pregnant women with somatic chronic medical conditions (SCMC) are at higher risk of adverse pregnancy outcomes and perinatal mental illness than women without SCMC. We aimed to describe the degree and content of worries in early pregnancy among Danish women with SCMC compared with women without SCMC. STUDY DESIGN: We conducted a cross-sectional study with self-reported questionnaires answered by 28,794 women from 2012─2019 during 1st trimester at a large university hospital in Denmark. MAIN OUTCOME MEASURES: We used the Cambridge Worry Scale (CWS). The outcomes of interest were the prevalence of major worry at item level (n/%) and the total CWS score (mean/SEM) as expression of the degree and content of worries. Univariate and multivariable regression analysis were performed. RESULTS: Women with SCMC reported a significantly higher total CWS score (aMD 1.50, 95% CI: 1.20-1.80). Women with SCMC were significantly more likely to report major worry in relation to own health (aOR 2.72, 95% CI: 2.43-3.08), the baby's health (aOR 1.40 95% CI 1.31-1.52), the process of giving birth (aOR 1.12, 95% CI: 1.04-1.21), the possibility of preterm labor (aOR 1.44, 95% CI: 1.28-1.63), and miscarriage (aOR 1.34, 95% CI: 1.24-1.43). CONCLUSION: Women with SCMC reported higher overall degree of worry during early pregnancy and an increased risk of major worry in relation to own health, pregnancy complications and giving birth. In antenatal care, these worries should be addressed by clinicians.

Degree of pregnancy planning and recommended pregnancy planning behavior among women with and without chronic medical conditions - A large hospital-based cross-sectional study.

INTRODUCTION: Pregnancy planning allows women to engage in pregnancy planning behaviors to optimize health status in the preconception period. Women with chronic medical conditions have a higher risk for adverse pregnancy outcomes and therefore preconception care is recommended. The aim was to compare pregnancy planning among women with and without chronic medical conditions, and to assess adherence to the recommended pregnancy planning behaviors on folic acid intake, physical activity and abstention from smoking and alcohol, among women with and without chronic medical conditions stratified by pregnancy planning. MATERIAL AND METHODS: A cross-sectional study with data from 28 794 pregnancies. Pregnancy planning was measured with the Swedish Pregnancy Planning Scale. Multiple Poisson regression with robust variance estimates was used to assess the associations between chronic medical condition (yes/no and main categories) and pregnancy planning, and chronic medical condition status and pregnancy planning behaviors stratified by pregnancy planning. RESULTS: In the study population, 74% reported high degree of pregnancy planning, and 22% had one or more chronic medical conditions. We found no overall association between chronic medical condition and pregnancy planning (adjusted rate ratio [RR] 1.00, 95% confidence interval [CI] 0.98-1.01). However, women with type 2 diabetes and mental illness were significantly less likely to plan their pregnancies than women without these conditions (aRR 0.73, 95% CI 0.61-0.88; aRR 0.91, 95% CI 0.87-0.96, respectively). Women with chronic medical conditions were more likely to adhere to the recommended planning behaviors; intake of folic acid, abstention from alcohol prior to pregnancy and no binge drinking in early pregnancy. CONCLUSIONS: Overall, pregnancies were highly planned. Women with chronic medical conditions did not show a higher degree of pregnancy planning than women without chronic medical conditions but were, however. more likely to adhere to the generally recommended pregnancy planning behaviors (ie intake of folic acid and abstention from alcohol intake). Only women with mental illness and type 2 diabetes reported a lower degree of pregnancy planning. It is important that we continuously address pregnancy planning and planning behaviors for both women with and women without chronic medical conditions, especially women with type 2 diabetes and mental illness.

Prevalence and predictors of maternal smoking prior to and during pregnancy in a regional Danish population: a cross-sectional study.

BACKGROUND: Maternal smoking is still a major public health problem posing the risk of several negative health outcomes for both the pregnant woman and her offspring. The prevalence of maternal smoking in Denmark and other high-income countries has decreased continuously since the 1980s, and a prevalence below 10% of women who continue to smoke during pregnancy has been reported in studies after 2010. Previous studies have shown that low socioeconomic status is associated with maternal smoking. Information from the Danish Birth Register about maternal smoking shows that the prevalence of women who report to smoke in pregnancy has decreased continuously with 23.3% who reported ever smoking in pregnancy in 2000, 12.9% in 2010 and 9.0% in 2017. The aim of this study was to estimate the prevalence of maternal smoking at the time of conception and at 20 weeks of gestation in a regional Danish population, to describe differences in maternal characteristics among smokers, quitters and never-smokers, and to estimate predictors of smoking at the time of conception. METHODS: A cross-sectional study was conducted among pregnant women receiving antenatal care at the Department of Obstetrics, Zealand University Hospital, Denmark from August 2015 to March 2016 (n = 566). The main outcome was smoking at the time of conception and at 20 weeks of gestation. The questionnaire also collected information about maternal, health-related and sociodemographic characteristics. Descriptive analysis was conducted, and multivariate logistic regression analysis was used to assess the potential associated predictors (adjusted odds ratio). RESULTS: The prevalence of self-reported smoking at the time of conception was 16% (n = 90) and 6% smoked at 20 weeks of gestation (n = 35), as 61% of smokers quit smoking during early pregnancy. Multiple logistic regression analysis showed that significant predictors for smoking at conception were the socioeconomic factors; ≤12 years of education, shift work and being unemployed. CONCLUSION: The prevalence of self-reported maternal smoking in this regional Danish population of pregnant women is lower than seen in previous studies. However, predictors for smoking at the time of conception remain to be factors of low socioeconomic status confirming a social inequality in maternal smoking. Women at risk of smoking during pregnancy must be identified in early pregnancy or even before pregnancy and be offered interventions to help them quit smoking.

Parental Rheumatoid Arthritis and Autism Spectrum Disorders in Offspring: A Danish Nationwide Cohort Study.

OBJECTIVE: Maternal rheumatoid arthritis (RA) has been associated with an increased risk of autism spectrum disorder (ASD) in the offspring. We assessed the potential influence of both maternal and paternal RA on the risk of ASD in offspring to disentangle the influence of genetic inheritance from other conditions potentially leading to fetal programming. METHOD: The nationwide cohort study included all children born alive from 1977 to 2008 in Denmark (N = 1,917,723). Cox regression models were used to calculate hazard rate ratios (HR) of ASD in offspring exposed to maternal or paternal RA, compared to unexposed children. RESULTS: Maternal RA was associated with an approximately 30% increased risk of ASD in the offspring (HR = 1.31 and 95% CI = 1.06-1.63). Also, paternal RA seemed to increase the risk of ASD by approximately 30% (HR = 1.33, 95% CI = 0.97-1.82). CONCLUSION: Our findings suggest maternal as well as paternal RA to be associated with an increased risk of ASD in the offspring, indicating that genetic factors associated with RA may also play a role in the etiology of ASD in children of parents with RA.

Parental rheumatoid arthritis and childhood epilepsy: A nationwide cohort study.

OBJECTIVE: To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy. METHODS: We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days-4 years), late childhood (5-15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010). RESULTS: Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13-1.60] and 1.26 [95% CI 1.13-1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92-1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81-1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26-2.86] vs HR 1.26 [95% CI 1.03-1.52], respectively [p = 0.16]). CONCLUSIONS: Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates that changes in the intrauterine environment may play a role.

Parental rheumatoid arthritis and long-term child morbidity: a nationwide cohort study.

OBJECTIVE: To estimate the influence of parental rheumatoid arthritis (RA) on child morbidity. DESIGN: Nationwide cohort study. SETTING: Individual linkage to nationwide Danish registries. PARTICIPANTS: All singletons born in Denmark during 1977-2008 (n=1 917 723) were followed for an average of 16 years. MAIN OUTCOME MEASURES: Adjusted HRs for child morbidity; that is, 11 main diagnostic groups and specific autoimmune diseases within the International Classification of Diseases 8th and 10th versions. RESULTS: Compared with unexposed children, children exposed to maternal RA ('clinical' and 'preclinical') (n=13 566) had up to 26% higher morbidity in 8 of 11 main diagnostic groups. Similar tendencies were found in children exposed to paternal RA ('clinical' and 'preclinical') (n=6330), with statistically significantly higher morbidity in 6 of 11 diagnostic groups. HRs were highest for autoimmune diseases with up to three times increased risk of juvenile idiopathic arthritis (HR, 95% CI 3.30, 2.71 to 4.03 and 2.97, 2.20 to 4.01) and increased risk of up to 40% of diabetes mellitus type 1 (HR, 95% CI 1.37, 1.12 to 1.66 and 1.44, 1.09 to 1.90) and up to 30% increased HR of asthma (HR, 95% CI 1.28, 1.20 to 1.36 and 1.15, 1.04 to 1.26). Conclusions were roughly similar for children exposed to maternal clinical RA and for children only followed up to 16 years of age. CONCLUSION: Children of parents with RA had consistent excess morbidity. If the associations reflect biological mechanisms, genetic factors seem to play an important role. These findings call for attention given to children of parents with RA.