ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases.

This European Respiratory Society/Thoracic Society of Australia and New Zealand statement outlines a review of the literature and expert opinion concerning the management of reproduction and pregnancy in women with airways diseases: asthma, cystic fibrosis (CF) and non-CF bronchiectasis. Many women with these diseases are now living into reproductive age, with some developing moderate-to-severe impairment of lung function in early adulthood. The statement covers aspects of fertility, management during pregnancy, effects of drugs, issues during delivery and the post-partum period, and patients' views about family planning, pregnancy and parenthood. The statement summarises current knowledge and proposes topics for future research, but does not make specific clinical recommendations.

Fertility outcomes in asthma: a clinical study of 245 women with unexplained infertility.

Evidence is increasing of an association between asthma and aspects of female reproduction. However, current knowledge is limited and furthermore relies on questionnaire studies or small populations. In a prospective observational cohort study to investigate whether time to pregnancy, the number of fertility treatments, and the number of successful pregnancies differ significantly between women with unexplained infertility with and without asthma.245 women with unexplained infertility (aged 23-45 years) underwent questionnaires and asthma and allergy testing while undergoing fertility treatment. 96 women entering the study had either a former doctor's diagnosis of asthma or were diagnosed with asthma when included. After inclusion they were followed for a minimum of 12 months in fertility treatment, until they had a successful pregnancy, stopped treatment, or the observation ended.The likelihood of achieving pregnancy was lower in women with asthma compared with those without asthma: median total time to pregnancy was 32.3 months in non-asthmatic women versus 55.6 months in those with asthma, hazard ratio 0.50 (95% confidence interval 0.34-0.74) p<0.001.Women with asthma had fewer successful pregnancies during fertility treatment, 39.6 versus 60.4% (p=0.002). Increasing age was of negative importance for expected time to pregnancy, especially among asthmatic women (interaction between age and asthma on time to pregnancy, p=0.001). Female asthmatics had a longer time to pregnancy and less often became pregnant than non-asthmatic women. Increasing age reduced the chances of conceiving especially among asthmatic women. The causal relationship between asthma and subfertility remains unclear.

Lower values of VEGF in endometrial secretion are a possible cause of subfertility in non-atopic asthmatic patients.

OBJECTIVE: Using endometrial secretion analysis, we assessed whether altered inflammatory cytokine levels can be detected in the uterine environment in asthma patients, thereby providing a possible cause of reduced fertility in asthmatics. METHODS: Forty-four unexplained infertile women (aged 28-44) underwent asthma and allergy testing, questionnaires, endometrial secretion and blood samples in the mid-secretory phase of the menstrual cycle (day 19-23) during assisted reproduction. Differences in cytokines and growth factors were analyzed. RESULTS: Mean log-VEGF in uteri was lower in asthma patients compared with controls (2.29 versus 2.70, p = 0.028). This was mainly due to lower values of VEGF among women with non-atopic asthma compared with women with atopic asthma (1.86 versus 2.72, p = 0.009) and with healthy controls (1.86 versus 2.70, p = 0.01). Asthma treatment status had no effect on VEGF levels in uteri. Serum high sensitivity CRP was negatively correlated with VEGF in endometrial secretions. No other significant correlations were observed between peripheral blood values and markers found in utero. CONCLUSION: Asthma is associated with lower values of VEGF in uterine endometrial secretions, which might affect the receptiveness of the endometrium and thereby increase time to pregnancy. The effect appears to be associated with non-atopic asthma with general increased systemic inflammation.

Asthma affects time to pregnancy and fertility: a register-based twin study.

Coexistence of infertility and asthma has been observed clinically. Therefore, we investigated the association between asthma and delayed pregnancy in a nationwide population-based cohort of twins. A cohort of 15 250 twins living in Denmark (aged 12-41 years) participated in a questionnaire study including questions about the presence of asthma and fertility. Differences in time to pregnancy and pregnancy outcome were analysed in subjects with asthma, allergy and in healthy individuals using multiple regression analysis. Asthma was associated with an increased time to pregnancy, the percentage of asthmatics with a time to pregnancy >1 year was 27% versus 21.6% for non-asthmatics (OR (95% CI) 1.31 (1.1-1.6); p=0.009). The association remained significant after adjustment for age, age at menarche, body mass index and socioeconomic status (OR (95% CI) 1.25 (1.0-1.6); p=0.05), and was more pronounced in those >30 years of age (32.2% versus 24.9%, OR (95% CI) 1.44 (1.1-1.9); p=0.04). Untreated asthmatics had a significant increased risk of prolonged time to pregnancy compared to healthy individuals (OR (95% CI) 1.79 (1.20-2.66); p=0.004), while asthmatics receiving any kind of treatment for asthma tended to have a shorter time to pregnancy than untreated asthmatics (OR 1.40; p=0.134). Asthma prolongs time to pregnancy. The negative effect of asthma on fertility increases with age and with disease intensity, indicating that a systemic disease characterised by systemic inflammation also can involve reproductive processes.

Age at menarche and risk of asthma: systematic review and meta-analysis.

BACKGROUND: Several studies have suggested a relationship between the age at menarche and risk of asthma development. OBJECTIVE: To conduct a systematic review and meta-analysis of the relationship between the age at menarche and the risk of asthma. METHODS: This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). A pre specified literature search strategy was used to identify studies of potential relevance and independent reviews were carried out by two authors. Raw data was pooled using the software package RevMan to calculate summary odds ratios. The risk of publication bias was assessed graphically by using a funnel plot and the robustness of the overall estimate obtained was assessed by using sensitivity analyses. RESULTS: The searches identified 61 potentially relevant articles of which seven articles, with a total of 22,859 subjects, matched the inclusion criteria for the meta-analysis. Pooling of the seven studies showed that girls with early menarche (<12 years) had an increased risk of asthma relative to girls with late menarche; random effects odds ratio = 1.37 (1.15-1.64), (p = 0.0005). Substantial heterogeneity was revealed (I(2) = 55%). Sensitivity analysis showed that the risk estimate was not markedly changed when excluding any of the studies. The funnel plot did not indicate publication bias. CONCLUSIONS: Early menarche appears to be associated with increased risk of asthma. Hormonal, immunological, genetic and environmental factors may act in a developmental context to explain this relationship. Future studies are warranted to further determine the mechanisms responsible for this observation.

Hormonal Contraceptives Are Associated With an Increase in Incidence of Asthma in Women.

BACKGROUND: Use of exogenous female sex hormones is associated with the development of asthma, but the question of whether the effect is protective or harmful remains unresolved. OBJECTIVE: To investigate whether initiation of hormonal contraceptive (HC) treatment was associated with development of asthma. METHODS: We performed a register-based, exposure-matched cohort study including women who initiated HC treatment of any kind between 10 and 40 years of age and compared the incidence of asthma with women who did not initiate HCs. Asthma was defined as 2 redeemed prescriptions of inhaled corticosteroids within 2 years. Data were analyzed using Cox regression models adjusted for income and urbanization. RESULTS: We included 184,046 women with a mean age of 15.5 years (SD 1.5 y), in which 30,669 initiated HC treatment and 153,377 did not. We found that initiation of HCs was associated with an increased hazard ratio (HR) of developing new asthma by 1.78 (95% CI 1.58-2.00; P < .001). The cumulative risk of new asthma was 2.7% after 3 years among users of HCs compared with 1.5% in nonusers. In the different subtypes of HCs, second- and third-generation contraceptives carried significant associations (second-generation HR 1.76; 95% CI 1.52-2.03; P < .001; third-generation HR 1.62 95% CI 1.23-2.12; P < .001). The association with increased incidence was seen only in women younger than 18 years. CONCLUSIONS: In this study, first-time users of HCs had an increased incidence of asthma compared with nonusers. Clinicians prescribing HCs should be aware that airway symptoms may develop.

Challenges in the successful management of asthma during conception, pregnancy and delivery.

Asthma and infertility are the most common disorders among women of reproductive age. Time to pregnancy is prolonged in women with asthma, and importantly, age seems to be a more important risk factor regarding fertility in women with asthma compared to women without asthma. Some data have shown a higher frequency of miscarriages in women with asthma, although the data are conflicting on this issue as studies have observed no association between asthma and pregnancy loss. Furthermore, studies have shown no negative effect of asthma on the total number of offspring. Pregnancy may, thus, have a significant impact on women with asthma, as well as on their offspring. The age of the women has an important impact on ability to conceive, but also for the pregnancy itself, with higher risk of uncontrolled asthma as well as asthma exacerbations with increasing age. Well-controlled asthma decreases the risk of maternal and fetal complications, while poorly controlled and undertreated asthma is associated with a range of risks for both mother and fetus. Asthma treatment should follow the general guidelines for asthma therapy, irrespective of pregnancy status, including treatment with inhaled corticosteroids, ß2-agonists and muscarinic antagonists. Targeted treatment with biologics for severe asthma seems to be without important adverse effects. The use of systemic corticosteroids may be associated with adverse events during the first trimester; however, an exacerbation with the associated risk of hypoxaemia is worse for the fetus. Best possible asthma control may be achieved using repeated measurements of fractional exhaled nitric oxide (F ENO), as the use of F ENO compared with symptoms registration only has been shown to reduce exacerbation rate. In conclusion, women with asthma should be encouraged to conceive at an early age, might experience miscarriages, but the number of offspring are the same as in women without asthma. Well treated asthma is important for the well-being of both the mother and the unborn fetus.

Inhaled anti-asthma therapies following hormone therapy in women: a nationwide cohort study.

Research question: Does menopausal hormone therapy (HT) with exogenous oestrogens and progestogens change the use of inhaled anti-asthma medications in women with asthma? Methods: In a population-based matched cohort study using the Danish registries, we included women with asthma aged 45-65 years from 1 June 1995 to 30 June 2018. We investigated whether HT with oestrogen and/or progestogens was associated with changes in use of inhaled anti-asthma therapies in the 12 months following initiation. We used exposure density matching to match exposed subjects with unexposed subjects on age, household income and level of education. An exposed subject was defined as receiving HT. We calculated mean dose of medications and odds ratios of increases in the 12 months following HT initiation. Results: We included 139 483 women with asthma, of whom 116 014 (83.2%) were unexposed subjects and 23 469 (16.8%) exposed subjects. Mean±sd age was 53.0±5.2 years. Initiation of HT was not consistently associated with increased mean doses of inhaled corticosteroids (ICS), or long- and short-acting ß2-agonists. Women receiving systemic oestrogens had increased odds ratios of large increases (>100 µg) in ICS at 6 months (OR 1.09; 95% CI 1.04-1.13; p<0.001) and 9 months (OR 1.07; 95% CI 1.03-1.12; p<0.001). Progestogens were protective against increases in ICS at 6 and 9 months (OR 0.87; 95% CI 0.82-0.93; p<0.001; and OR 0.86; 95% CI 0.81-0.91; p<0.001). Conclusion: Initiation of HT did not change the use of inhaled medications in asthma. However, detrimental effects of oestrogen, as well as beneficial effects of progestogens, cannot be excluded.

Hormone Replacement Therapy and Development of New Asthma.

BACKGROUND: Hormone replacement therapy (HRT) is prescribed to millions of women worldwide. Previous studies have suggested that HRT has both protective and harmful effects in asthma. RESEARCH QUESTION: Is HRT in menopause associated with new development of asthma? STUDY DESIGN AND METHODS: We undertook a nested case-control study based on the Danish registers from June 1, 1995, through December 31, 2018. A diagnosis of asthma was defined as two redeemed prescriptions of inhaled corticosteroids within 2 years. HRT was defined as two redeemed prescriptions of female sex hormones within 6 months. Data were analyzed using a conditional logistic regression model. RESULTS: We included 34,533 women with asthma vs 345,116 women without asthma between 40 and 65 years of age. In a multivariate analysis adjusted for age, household income, and educational level, active HRT resulted in a hazard ratio (HR) of 1.63 (95% CI, 1.55-1.71; P < .001) of new asthma development. Women with asthma who terminated HRT were likely to discontinue their asthma treatment subsequently (HR, 2.12; 95% CI, 1.94-2.33; P < .001). INTERPRETATION: HRT seems to play a role in the development of asthma in mature women. Clinicians prescribing HRT and women receiving HRT should be aware that new airway symptoms can develop, and discontinuation of HRT should be considered.

Fertility Treatment Resulting in Live Births in Women with Asthma - Associated with Perennial Allergy?

BACKGROUND: Asthma has been linked with prolonged time to pregnancy compared to healthy controls, also asthma has been linked to a higher need for fertility treatment. However, knowledge of the possible association between allergy and need for fertility treatment is limited. Our aim was to explore a possible difference in having had fertility treatment in women with asthma and live births in those with perennial allergy (animals, fungi and dust mites) compared to no allergy/seasonal allergy. The primary outcome of interest was fertility treatment. PATIENTS AND METHODS: Women enrolled in the Management of Asthma during Pregnancy (MAP) program at Hvidovre Hospital, DK, were included in the present analysis provided they fulfilled the following criteria: 1) diagnosed with asthma and current anti-asthma therapy and 2) first visit to the respiratory outpatient clinic within the first 18 weeks of pregnancy. Participants were divided into two groups: asthma with perennial allergy (cases) and asthma with seasonal/no allergy (controls). Logistic regression analysis was applied, and findings expressed as odds ratios (OR). RESULTS: Among women with asthma and perennial allergy (n=544 cases), 13.8% (n=75) had fertility treatment, compared to only 10.1% (n=39) among women with asthma and seasonal/no allergy (n=388, controls) (OR 1.43, 95% CI 0.95-2.16, p=0.087). This association remained statistically insignificant after adjusting for confounders, including BMI (OR 1.19, 95% CI 0.77-1.84, p=0.433). In women ≥35 years of age, 28% (n=44) and 20% (n=19), respectively, among cases and controls had fertility treatment (OR 1.60, 95% CI 0.87-2.94, p=0.132), and likewise, statistically insignificant after adjusting for confounders (OR 1.41, 95% CI 0.74-2.69, p<0.293). CONCLUSION: In women with asthma and live births, our study revealed a trend towards an association between perennial allergy and a higher need for fertility treatment compared to seasonal/no allergy.

Treatment with the anti-IgE monoclonal antibody omalizumab in women with asthma undergoing fertility treatment: a proof-of-concept study-The PRO-ART study protocol.

INTRODUCTION: Asthma is associated with prolonged time to pregnancy and a higher need for fertility treatment. However, the mechanism underlying this association remains incompletely understood. Previous research points to asthma-driven systemic inflammation also affecting the reproductive organs and thereby fertility. The aim of this study was to determine if treatment with omalizumab prior to fertility treatment will increase pregnancy rate among women with asthma by decreasing the systemic asthma-related inflammation and, by that, to provide insight into the underlying mechanisms. METHODS AND ANALYSIS: This is an ongoing prospective multicentre randomised controlled trial planned to enrol 180 women with asthma recruited from fertility clinics in Denmark. The patients are randomised 1:1 to either omalizumab or placebo. The primary endpoint is the difference in pregnancy rate confirmed with ultrasound at gestational week 7 of pregnancy. The secondary endpoints are change in sputum and blood eosinophil cell count, change in biomarkers, change in microbiota, together with rate of pregnancy loss, frequency of malformations, pre-eclampsia, preterm birth, birth weight, small for gestational age and perinatal death between groups. ETHICS AND DISSEMINATION: The methods used in this study are of low risk, but if successful, our findings will have a large impact on a large group of patients as infertility and asthma are the most common chronic diseases among the young population. The study has been approved by the Ethics Committee-Danish national research ethics committee (H-18016605) and the Danish Medicines Agency (EudraCT no: 2018-001137-41) and the Danish Data Protection Agency (journal number: VD-2018486 and I-Suite number 6745). The test results will be published regardless of whether they are positive, negative or inconclusive. Publication in international peer-reviewed scientific journals is planned. TRIAL REGISTRATION NUMBER: NCT03727971.

Coexistence of asthma and polycystic ovary syndrome: A concise review.

Asthma may be associated with polycystic ovary syndrome (PCOS), and possibly patients with PCOS have a more severe type of asthma. The purpose of this systematic literature review is to summarize evidence of a coexistense of PCOS and asthma using the available literature. The search was completed on 01.01.2016. English language articles were retrieved using the search terms 'Asthma' AND 'PCOS', 'Asthma' AND 'systemic inflammation', 'Asthma' AND 'metabolic syndrome', 'asthma' AND 'gynaecology', 'PCOS' AND 'systemic inflammation', 'PCOS' AND 'metabolic syndrome', 'PCOS' AND 'allergy'. Five papers meeting prespecified search criteria were found of which two were registry studies of relevance. The current literature supports a coexistense of PCOS and asthma and gives us an indication of the causes for the possible link between PCOS and asthma. Further research in the area must be conducted to determine the exact nature and magnitude of the association.

Early menarche is associated with increased risk of asthma: Prospective population-based study of twins.

AIM: To examine the association between early menarche and risk of post-menarcheal asthma. METHODS: Using data from two multidisciplinary questionnaire surveys, conducted eight years apart, we prospectively studied 10,648 female twins, 12-41 years of age, from the nationwide Danish Twin Registry. Early menarche was defined as menarche before 12 years of age. We performed a cohort analysis and a co-twin control analysis including twin pairs discordant for incident asthma. RESULTS: Early menarche was observed in 9.3% of the individuals. The eight-year cumulative incidence of asthma was higher in girls with early menarche compared to girls without early menarche (7.4 vs. 4.5%), OR = 1.71 (1.31-2.22), p < 0.001; also after adjustment for BMI, current age, physical activity, education, and smoking, OR = 1.53 (1.15-2.04), p = 0.003. The unadjusted risk of asthma was increased by 8% (1-15%), p = 0.041 per year earlier menarche occurred. Among 167 twin pairs discordant for incident asthma, there was a non-significant tendency towards early menarche being more common in the asthmatic than the non-asthmatic co-twin (12.0 vs. 9.6%), OR = 1.57 (0.61-4.05), p = 0.350. The risk of asthma was not uniform in discordant monozygotic and dizygotic twins. CONCLUSION: Early menarche is associated with increased risk of asthma among Danish female twins independently of BMI, age, physical activity, educational level and smoking. Results indicate a complex relationship possibly mediated through innate and non-genetic effects.

Female asthma has a negative effect on fertility: what is the connection?

Reproductive changes such as impaired fertility and adverse pregnancy outcomes have been related to female asthma. We recently found that time to pregnancy is prolonged in asthmatic females especially in women with moderate to severe asthma and in those above 30 years of age. Despite their reproductive difficulties the asthmatics ultimately conceived just as many biological children as healthy throughout their reproductive lives. This knowledge therefore raises questions about how asthma affects fertility pathophysiologically. The purpose of this review is to describe the existing knowledge in this field and suggest hypotheses of causal relationships, which may form the basis for future studies in this field. The aim is, in particular, in the literature to examine whether there is any evidence to suggest that the systemic inflammation that characterizes asthma, can affect fertility. The issue is potentially clinically important for asthmatic, infertile individuals and society because treatment of the general systemic inflammation associated with the asthmatic disease combined with hormone stimulation might be the optimal target for an effective infertility therapy, possibly decreasing the need for in vitro fertilization.