Tolerance induction through early feeding to prevent food allergy in infants and children with sensitization against food allergens (TIFFANI): rationale, study design, and methods of a randomized controlled trial.

BACKGROUND: Children with sensitization against foods have to be orally food-challenged before eating these foods for the first time. However, the waiting time for an oral food challenge (OFC) in Germany is about 3-6 months. In contrast, there are hints that an early introduction of allergenic foods might be protective regarding the development of food allergy. The aim of this clinical trial is therefore to investigate, whether an introduction and regular consumption of small amounts of food allergens is safe and will result in an increase of tolerance in children with sensitization against food allergens with unknown clinical relevance. METHODS: In this randomized, placebo-controlled, double-blind, single-center trial, 138 children (8 months to 4 years of age) sensitized to the target allergen(s) hen's egg, cow's milk, peanuts, and/or hazelnuts with unknown clinical relevance will be randomized in a 1:1 ratio to either an active or a placebo group, daily receiving a rusk-like biscuit powder with or without the target allergen(s) for 3-6 months until an OFC will be performed in routine diagnostics. The primary endpoint is an IgE-mediated food allergy to the primary target allergen, after the interventional period. DISCUSSION: Children with sensitization against food allergens with unknown clinical relevance often have to avoid the corresponding foods for several months until an OFC is performed. Therefore, the "window of opportunity" for an early preventive introduction of allergenic foods might be missed. This trial will assess whether an introduction of small allergen amounts will favor tolerance development in these children. TRIAL REGISTRATION: German Clinical Trials Register DRKS00032769. Registered on 02 October 2023.

Public Attitudes Toward Ethics and Practices in End-of-Life Decision-Making for Neonates.

Importance: Attitudes toward end-of-life decision-making in neonatology have been studied in physicians and other health care professionals and are mostly shaped by their clinical education and work experiences. In contrast, attitudes among the general public have not yet been investigated. Objective: To assess (1) attitudes in the general public toward euthanasia and withdrawal of life-prolonging treatment in neonates with severe life-limiting conditions, (2) knowledge of current German recommendations, and (3) values in the German society regarding ethical issues and proxy decisions at the beginning of life. Design, Setting, and Participants: This cross-sectional study was performed in Germany and used an exploratory design to analyze responses to an interview conducted by an independent, established commissioned polling institute in March and April 2022. Participants were 16 years or older, with German language fluency and comprehension and living in Germany. Main Outcomes and Measures: Knowledge about recommendations for euthanasia and withdrawal of life-prolonging treatment as well as personal attitudes toward (1) euthanasia and withdrawal of life-prolonging treatment and (2) surrogate end-of-life decision-making for newborn infants were assessed. Results: The study included 2116 participants (1077 females [50.9%]; mean [SD] age 52.1 [18.7] years). Of the participants, 16.8% (311 of 1851) reported knowing the German recommendations for euthanasia and withdrawal of life-prolonging treatment for neonates. Euthanasia and withdrawal of life-prolonging treatment were supported by 64.7% (1369 of 2116) and 77.9% (1649 of 2116) of respondents, respectively. Shared decision-making between parents and physicians for neonates in end-of-life situations was supported by 65.6% of participants (1388). In situations where shared decision-making was not possible, 73.4% of respondents (1019 of 1388) put the ultimate decision to the parents. The magnitude of the associations was low between sociodemographic factors and views on ethical issues and customary practices involved in end-of-life decisions for neonates. Conclusions and Relevance: Results of this cross-sectional study suggested that most respondents were not aware of the national German recommendations for euthanasia and withdrawal of life-prolonging treatment for sick and extremely preterm newborns. When counseling parents of periviable newborns, clinicians may need to exert more effort in explaining the legal and ethical framework; a highly individualized approach is warranted.

[Ethical Attitudes and Handling in Prenatal Conflict Situations - A Survey among Obstetricians and Prenatal Diagnosticians in Germany]. / Ethische Haltungen und Umgang in pränatalen Konfliktsituationen ­ eine Umfrage unter Geburtshelfern und Pränataldiagnostikern in Deutschland.

OBJECTIVE: Various studies have shown that belonging to a professional group has an influence on ethical attitudes. The aim of this study was to assess and compare the attitudes and approaches of obstetrical specialists and prenatal diagnosticians in prenatal conflict situations. METHODS: Explorative cross-sectional online survey among tertiary perinatal care centers and prenatal diagnosticians with DEGUM Level II/III in Germany. The questionnaire included questions on ethical attitudes in the perinatal context and a case presentation of a fetal hypoplastic left heart syndrome. RESULTS: The response rate was 57.1% (310/543). 55.5% of the respondents practiced both obstetrics and prenatal diagnostics, 24.5% exclusively prenatal diagnostics, and 14.2% purely obstetrics. 27% agreed with the statement "An uncertain prognosis justifies pregnancy termination". For complex fetal malformations joint interdisciplinary counseling was advocated by 98.3%. Addressing the option of postnatal palliative treatment in a case of a hypoplastic left heart syndrome was accepted by 84.3% across all professional groups, while mentioning fetocide was more frequently cited as an option by prenatal diagnosticians than by obstetricians (57.7% vs. 34.1%). CONCLUSION: Interdisciplinary prenatal parental counseling in complex fetal malformations is uniformly advocated by prenatal diagnosticians and obstetricians in Germany. However, different ethical attitudes appear among specialists groups with regard to the option of termination of pregnancy.

Self-care strategies for medical students: an uncontrolled mixed-methods evaluation of a mind-body-medicine group course.

BACKGROUND: High stress during medical education and its detrimental effects on student health is well documented. This exploratory evaluation study assesses a 10-week Mind-Body-Medicine student course, created to promote student self-care at Charité Universitätsmedizin Berlin, Germany. METHODS: During 2012-2019, uncontrolled quantitative and qualitative data were gathered from 112 student participants. Outcomes including changes in perceived stress (PSS), mindfulness (FMI/MAAS), self-reflection (GRAS), self-efficacy (GSE), empathy (SPF), and health-related quality of life (SF-12) were measured between the first (T0) and last sessions (T1). Qualitative data were obtained in focus groups at course completion and triangulated with quantitative data. RESULTS: Quantitative outcomes showed decreases in perceived stress and increased self-efficacy, mindfulness, self-reflection, and empathy. In focus groups, students reported greater abilities to self-regulate stressful experiences, personal growth and new insights into integrative medicine. Triangulation grounded these effects of MBM practice in its social context, creating an interdependent dynamic between experiences of self and others. CONCLUSION: After completing an MBM course, students reported reduced perceived stress, increased self-efficacy, mindfulness, empathy and positive engagement with integrative concepts of doctor-patient relationships. Further research with larger randomized confirmatory studies is needed to validate these benefits.

Hypnotherapy, Intermittent Fasting, and Exercise Group Programs in Atopic Dermatitis: A Randomized Controlled Explorative Clinical Trial During the COVID-19 Pandemic.

Background: Patients with atopic dermatitis (AD) frequently use healthy lifestyle behaviors, although their benefits are unclear. This study's aim was to investigate the effectiveness of hypnotherapy, fasting with diet adjustments, and exercise in AD patients. Methods: In a four-armed randomized controlled monocenter open explorative clinical trial, adult patients with mild-to-moderate severe AD underwent, over 16 weeks, a five-session hypnotherapy group program (HTP), a five-session intermittent fasting with diet adjustment group program (IFDP), a five-session exercise group program (EP), or no study intervention (control) as add-on to topical corticosteroid use if required. Endpoints included subjectively perceived itching on a visual analogue scale (VAS, 0-100 mm); disease severity by SCORing Atopic Dermatitis (SCORAD); and adverse events (AEs). Endpoints were analyzed descriptively in the Full Analysis Set (FAS). Due to the coronavirus disease 2019 (COVID-19) pandemic, relevant changes to the study protocol included online in addition to "in-presence" group interventions, closing the study arm EP and premature trial termination before randomization of 120 intended patients. Results: During the COVID-19 pandemic, study recruitment was poor. The FAS included 20 patients (17 female) with 35.0 ± 12.1 (mean ± standard deviation [SD]) years of age. At baseline, mean ± SD for HTP (n = 6), IFDP (n = 4), EP (n = 1), and control (n = 9) were VAS itching 63.2 ± 18.0, 65.0 ± 13.9, 43.0 mm, 62.1 ± 17.3; SCORAD 43.0 ± 13.6, 47.0 ± 21.0, 60.3, 39.1 ± 15.6. After 16 weeks, endpoints were VAS itching 26.0 ± 16.4, 31.7 ± 9.9, 23.0 mm, 39.3 ± 27.0; SCORAD 24.1 ± 12.2, 29.1 ± 19.1, 49.1, 25.5 ± 14.4. No serious AEs related to the interventions were observed. Conclusion: Despite very small groups, study results indicated potential beneficial changes to baseline in perceived itching intensity, disease severity, and disease-specific quality of life for HTP and IFDP. Therefore, further clinical trials should be performed investigating the effectiveness and safety of all interventions. Clinical Trial Registration: January 31, 2020 German Clinical Trials Register (DRKS): DRKS00020557, Universal Trial Number (UTN): U1111-1247-1512.

Health-Related Self-Care Strategies and Coping Resources During the COVID-19 Pandemic: An Online-Based Cross-Sectional Study.

Background: Complementary medicine (CM) is often used as an opportunity for preventive health measures and supportive self-care practices. This study aimed to explore the use of self-care practices and preventive health strategies and the aspects of the experienced emotions during the COVID-19 pandemic in a population with an affinity for CM. Methods: The authors conducted an exploratory cross-sectional study using an anonymous 41-item online survey in the German language. The survey respondents were recruited among adults with an affinity for CM (e.g., as targeted through their memberships in CM associations) from September 2020 to February 2021. A selection of self-care methods, mainly from CM, was presented in the questionnaire. Numerical rating scales (NRSs), ranging from 0 = minimum to 10 = maximum, were used to measure the intensity of different emotions experienced during the pandemic. Statistical analysis was carried out descriptively. Results: A total of 1605 participants (80.6% female; mean age: 55.4 ± 12.6 [SD] years; 43.9% holding a university degree) were included. The use of self-care methods for health promotion during the pandemic was reported by 86.8% of the respondents. Respondents favored staying in nature (85.6%), healthy nutrition (85.6%), and physical activities (83.6%). More than 60% of the respondents made use of vitamin C and/or D, herbal medicines, nutritional supplements, relaxation techniques, breathing exercises, homeopathy, or meditation for health promotion. The analysis of emotional status by NRS (0-10) revealed the lowest mean ± SD (standard deviation) for "feeling lonely" (2.6 ± 2.9) and "feeling anxious" (2.8 ± 2.6), and the highest mean for "feeling connected to others" (6.2 ± 2.5) and "well-being" (5.8 ± 2.4). Conclusions: Participants used a wide variety of self-care methods and prevention strategies to promote their health during the COVID-19 pandemic and showed, overall, a balanced emotional status. Further research should include a control group representative of the general population, to investigate the possible impact of self-care strategies. Clinical Trial Registration Number: "Deutsches Register Klinischer Studien" (German Clinical Trial Register); registration number: DRKS00022909.

Acupuncture and osteopathic medicine for atopic dermatitis: a three-armed, randomized controlled explorative clinical trial.

BACKGROUND: Patients with atopic dermatitis (AD) frequently use acupuncture (ACU) and osteopathic medicine (OM), although their therapeutic benefits are unclear. AIM: To investigate the effectiveness of ACU and OM in patients with AD. METHODS: In a three-armed, single-centre, randomized controlled open explorative clinical trial, adult patients with AD received ACU, OM or no study intervention (control group; CG) plus routine care. Outcomes included disease severity (SCORing Atopic Dermatitis; SCORAD), itching intensity (visual analogue scale; VAS), frequency of topical corticosteroid (TCS) use over 7 days and cost-effectiveness. Endpoints were analysed by analysis of covariance adjusted for the respective baseline value and TCS use. RESULTS: Overall, 121 patients (92 women, 29 men) with a mean ± SD age of 31.4 ± 10.5 years were randomized. After 12 weeks, the adjusted means (95% CI) for ACU, OM and control were, respectively, 22.3 (18.3-26.3), 26.4 (22.6-30.2) and 23.7 (19.9-27.5) for SCORAD (P = 0.32); 27.9 (19.5-36.4), 35.0 (26.9-43.0) and 42.3 (34.7-50.0) for VAS itching (P < 0.05); and 2.3 (0.8-3.9), 1.9 (0.4-3.5) and 4.3 (2.6-6.0), for TCS use (P = 0.10). ACU and OM were not cost-effective compared with the CG. CONCLUSION: Although no differences in disease severity were found, our findings indicate that ACU might reduce itching in patients with AD. Furthermore, ACU and OM showed a trend towards reducing TCS use.

Feasibility and Possible Effects of Mindful Walking and Moderate Walking in Breast Cancer Survivors: A Randomized Controlled Pilot Study With a Nested Qualitative Study Part.

INTRODUCTION: Breast cancer (BC) survivors often suffer from disease- and therapy-related long-term side-effects. The study aim was to explore the feasibility, adherence, and individual experiences as well as possible effects of 2 different walking interventions in BC patients. METHODS: This randomized controlled, pragmatic pilot trial included a qualitative study component. BC patients were randomized to either mindful walking (MFW) with mindfulness exercises and walking or moderate walking (MW) alone in weekly group sessions over 8 weeks. After 8 and 16 weeks, satisfaction, and self-perceived effectiveness as well as different health-related outcomes including health-related (WHOQOL-BREF) and disease-specific quality of life (FACT-G), perceived stress (PSQ) and cancer-related fatigue (CFS-D) were assessed. ANCOVA was used to evaluate differences in study outcomes. Qualitative data included 4 focus group interviews including 20 patients and were analyzed using a directed qualitative content analysis approach. RESULTS: Altogether, 51 women (mean age 55.8 years (SD 10.9)) were randomized (n = 24 MFW; n = 27 MW). Both groups would recommend the course to other BC patients (MFW 88.9%; MW 95.2%) and showed possible improvements from baseline to week 8, without statistically significant difference between groups: WHOQOL-BREF (MFW: adjusted mean 65.4 (95% confidence interval (CI), 57.1-73.7); MW: 61.6 (53.6-69.6)); FACT-G (MFW: 76.0 (71.5-80.5); MW: 73.0 (68.5-77.4)); PSQ (MFW: 45.3 (40.5-50.1); MW: 45.4 (40.8-50.0)); CFS-D (MFW: 24.3 (20.8-27.8); MW: 25.5 (22.1-28.8)). Improvements lasted until the 16-weeks follow-up. The qualitative analysis suggested that MFW primarily promoted mindfulness, self-care, and acceptability in BC patients, whereas MW activated and empowered the patients as a result of the physical exercise. CONCLUSION: Both study interventions were positively evaluated by patients and showed possible pre-post effects in disease-specific health-related outcomes without differences between groups. The qualitative analysis results indicate that different resources and coping strategies were addressed by the 2 study interventions. TRIAL REGISTRATION: DKRS00011521; prospectively registered 21.12.2016; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011521.

Osteopathic Medicine in Four Chronic Musculoskeletal Pain Diseases: An Observational Trial with Follow-Up.

BACKGROUND AND AIM: Patients with chronic musculoskeletal pain diseases (CMPDs) often use osteopathic medicine (OM), although the changes in patients with pain diseases are still insufficiently investigated. This study aimed to observe changes along and after OM in addition to routine care on pain, functioning, and quality of life in patients with four CMPDs. METHODS: In this observational trial with follow-up, patients suffering from chronic neck pain (CNP, n = 10), chronic low back pain (CLBP, n = 10), chronic shoulder pain (CSP, n = 10), or chronic knee pain (CKP, n = 10) received up to six OM sessions in addition to routine care. RESULTS: A total of 40 patients (73% female, mean age 47.7 ± 8.3 years, mean pain intensity 59.4 ± 12.5 mm, measured by a visual analog scale [VAS] 0-100 mm) were included. After 26 weeks, there was an improvement in the VAS pain score in the whole population (mean difference to baseline -33.1 mm [95% CI -40.5 to -25.7]), as well in the patients with the four diseases: CNP (-33.7 mm [-54.7 to -12.6]), CLBP (-28.2 mm [-47.9 to -8.4]), CSP (-32.4 [-46.8 to -18.0]), and CKP (-38.1 mm [-49.1 to -27.0]). Regarding disease-specific outcomes, we found improvements in CNP, as measured by the neck disability index (scale 0-50; mean difference -3.6 [-9.0 to 1.9]), CLBP, as measured by the low back pain rating scale (scale 0-60; -3.4 [-12.5 to 5.7]), CSP, as measured by the disabilities of the arm, shoulder and hand score (scale 0-100; -13.4 [-23.1 to -3.7]), and CKP, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (scale 0-96; -13.0 [-23.5 to -2.5]). These improvements persisted through week 52. No adverse events were observed. CONCLUSION: The study observed beneficial changes along and after the OM treatment in addition to routine care in patients with four different CMPDs. High-quality, multicenter randomized controlled trials are strongly needed to compare the effectiveness of OM and standard care interventions in treating CMPDs in the future. We have provided sufficient data for sample size calculations for these trials.

Acupressure in patients with seasonal allergic rhinitis: a randomized controlled exploratory trial.

BACKGROUND: Acupuncture has shown beneficial effects for seasonal allergic rhinitis (SAR); however, it is time and cost intensive. We investigated feasibility and effects of self-administered body acupressure as a self-care technique that stimulates acupuncture points with manual pressure in SAR patients. METHODS: We conducted a two-armed randomized controlled exploratory trial to compare effects of self-administered acupressure over 4 weeks at five acupuncture points plus rescue medication (RM) with cetirizine compared to RM alone in SAR patients. Among other outcome parameters, we assessed disease-related quality of life (Rhinitis Quality of Life Questionnaire [RQLQ]), overall SAR symptoms by a visual analogue scale (VAS) and a rescue medication score (RMS) after 4 and 8 weeks. RESULTS: Forty-one SAR patients (mean age 38.5 ± 10.0 years, n = 21, 51.2% women) were randomized. Compared to RM alone (n = 21), acupressure plus RM (n = 20) was associated with relevant improvements after 4 weeks, shown by the difference between groups in adjusted means of RQLQ: - 0.9 points (95% CI - 1.6 to - 0.2; p = 0.011) and VAS overall SAR symptoms: - 21.6 mm (95% CI - 36.3 to - 6.8; p = 0.005). The RMS was lower in the acupressure group than in the control group: 1.9 points (95% CI - 3.8 to - 0.1; p = 0.120). Group differences decreased slightly until week 8. The acupressure was feasible and safe. CONCLUSION: Results of this exploratory study indicate that self-applied acupressure is feasible, may improve disease-specific quality of life and reduce disease-related symptoms as well as anti-allergic medication intake in SAR patients. High-quality confirmatory studies including a sham-control group are needed in the future. Trial registration DRKS-ID: DRKS00014310. Date of registration in DRKS: 2018/04/24. Investigator sponsored/initiated trial (IST/IIT): yes. Ethics approval/approval of the ethics committee: Approved (leading) Ethics Committee No. EA1/033/18, Ethik-Kommission der Charité -Universitätsmedizin Berlin. URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00014310.

Sex-Specific Long-Term Trends in Length of Hospital Stay, Postmenstrual Age at Discharge, and Survival in Very Low Birth Weight Infants.

INTRODUCTION: In very low birth weight (<1,500 g, VLBW) infants, morbidity and mortality have decreased substantially during the past decades, and both are known to be lower in girls than in boys. In this study, we assessed sex-specific changes over time in length of hospital stay (LOHS) and postmenstrual age at discharge (PAD), in addition to survival in VLBW infants. METHODS: This is a single-center retrospective cohort analysis based on quality assurance data of VLBW infants born from 1978 to 2018. Estimation of sex-specific LOHS over time was based on infants discharged home from neonatal care or deceased. Estimation of sex-specific PAD over time was based on infants discharged home exclusively. Analysis of in-hospital survival was performed for all VLBW infants. RESULTS: In 4,336 of 4,499 VLBW infants admitted from 1978 to 2018 with complete data (96.4%), survival rates improved between 1978-1982 and 1993-1997 (70.8 vs. 88.3%; hazard ratio (HR) 0.20, 95% confidence interval 0.14, 0.30) and remained stable thereafter. Boys had consistently higher mortality rates than girls (15 vs. 12%, HR 1.23 [1.05, 1.45]). Nonsurviving boys died later compared to nonsurviving girls (adjusted mean survival time 23.0 [18.0, 27.9] vs. 20.7 [15.0, 26.3] days). LOHS and PAD assessed in 3,166 survivors displayed a continuous decrease over time (1978-1982 vs. 2013-2018: LOHS days 82.9 [79.3, 86.5] vs. 60.3 [58.4, 62.1] days); PAD 40.4 (39.9, 40.9) vs. 37.4 [37.1, 37.6] weeks). Girls had shorter LOHS than boys (69.4 [68.0, 70.8] vs. 73.0 [71.6, 74.4] days) and were discharged with lower PAD (38.6 [38.4, 38.8] vs. 39.2 [39.0, 39.4] weeks). DISCUSSION/CONCLUSIONS: LOHS and PAD decreased over the last 40 years, while survival rates improved. Male sex was associated with longer LOHS, higher PAD, and higher mortality rates.

Fetotoxic risk of AT1 blockers exceeds that of angiotensin-converting enzyme inhibitors: an observational study.

OBJECTIVE: The fetotoxic potential of prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been known for many years. Symptoms range from transient oligohydramnios to neonatal anuria and permanent renal damage, joint contractures, hypocalvaria, lung hypoplasia and intrauterine or neonatal death. This study aims to investigate the critical gestational time for renin-angiotensin system inhibitor (RAS-I)-induced fetopathy, to quantify the fetopathy risk and to evaluate factors associated with the occurrence and severity of fetopathy. METHODS: Prospectively and retrospectively ascertained RAS-I exposed pregnancies from the databases of six teratology information services were analyzed. RESULTS: Eighty-nine pregnancies with ACE-I and 101 with ARB exposure beyond the first trimester were identified. Fifty-nine of these 190 pregnancies were classified as having evidence of RAS-I fetopathy. All pregnancies affected with fetopathy were exposed after 20 0/7 gestational weeks. Limited to prospectively enrolled cases with exposure at least 20 0/7 gestational weeks, the rate of fetopathy was 3.2% for ACE-I and 29.2% for ARB. The chance of recovery of amniotic fluid volume was higher with RAS-I discontinuation before 30 gestational weeks and with a longer exposure-free interval before delivery. CONCLUSION: Exposure to ARBs is associated with a higher fetopathy risk than exposure to ACE-Is. RAS-I should ideally be discontinued prior to pregnancy or immediately after recognition of pregnancy. Because symptoms may improve in cases of RAS-I-induced oligohydramnios, pregnancy should be maintained as long as there is fetal well being. Physicians and patients need to be alerted to the fetotoxic risks of RAS-I.

Increased rate of birth defects after first trimester use of angiotensin converting enzyme inhibitors - Treatment or hypertension related? An observational cohort study.

OBJECTIVES: To analyze the risk of spontaneous abortions and major birth defects in pregnancies of women treated with angiotensin converting enzyme inhibitors (ACEIs) during the first trimester. STUDY DESIGN: Observational cohort study of prospectively ascertained pregnancies from the German Embryotox pharmacovigilance institute. Pregnancy outcomes after maternal exposure to ACEIs during the first trimester were compared with pregnancies without antihypertensive treatment. In a sensitivity analysis, ACEI exposed hypertensive women were compared with hypertensive women on methyldopa. RESULTS: The risk of spontaneous abortion among 329 ACEI exposed women was not increased compared to 654 women without antihypertensive treatment (adjusted hazard ratio 1.20, 95% confidence interval (CI) 0.74-1.92), whereas the risk for major birth defects (14/255; 5.5% vs. 19/567; 3.4%) was significantly increased (adjusted odds ratio 2.41, 95% CI 1.07-5.43). In contrast, birth defect rates were not significantly different between hypertensive women on ACEIs and hypertensive women on methyldopa. In addition, we did not observe a distinct pattern of birth defects among retrospectively ascertained pregnancies after ACEI exposure during the first trimester. CONCLUSIONS: Women with hypertension treated with ACEIs in early pregnancy are at higher risk for major birth defects, which may be explained by other factors associated with maternal hypertension. Women (inadvertently) exposed during early pregnancy may be reassured and treatment switched to antihypertensive drugs recommended for pregnancy.

Pregnancy outcome after first trimester use of angiotensin AT1 receptor blockers: an observational cohort study.

BACKGROUND: Ongoing discussion about the safety of renin-angiotensin inhibitors in the first trimester and limited data on pregnancy outcomes after exposure to angiotensin AT1 receptor blockers (ARBs). METHODS: Observational cohort study compares outcomes of 215 prospectively ascertained pregnancies with first trimester exposure to ARBs with 642 non-hypertensive pregnancies. RESULTS: The rate of major birth defects in the ARB cohort (9/168, 5.4%) was higher than in the comparison group (17/570, 3%), but not significantly increased (ORadj 1.9, 95% CI 0.7-4.9). There was no distinct pattern of anomalies among infants with birth defects. The risk of spontaneous abortions was not increased (HRadj 0.9, 95% CI 0.5-1.6), although the cumulative incidence was in the upper normal range (0.22, 95% CI 0.15-0.32). Higher rates of prematurity (ORadj 3.0; 95% CI 1.7-5.1) and a reduced birth weight after adjustment for sex and gestational age were observed. There was no evidence for an increased risk for major birth defects, spontaneous abortions, or preterm birth in a sensitivity analysis comparing ARB exposed hypertensive women to hypertensive women without ARB exposure during the first trimester. CONCLUSION: Our study supports the hypothesis that ARBs are not major teratogens. Patients inadvertently exposed to ARBs during the early pregnancy may be reassured. Nevertheless, women planning pregnancy should avoid ARBs. In selected cases, ARBs might be continued under careful monitoring of menstrual cycle and discontinued as soon as pregnancy is recognized.

Safety of diclofenac use during early pregnancy: A prospective observational cohort study.

Diclofenac is a widely used analgesic so that exposure during pregnancy may frequently occur. Most publications have evaluated the safety of NSAIDs on pregnancy outcome as a group of substances. Specific data on diclofenac are rare. This observational cohort study used the German Embryotox pharmacovigilance database to assess the risk of major birth defects and spontaneous abortion after first trimester exposure to diclofenac. A group of 260 women who took diclofenac during first trimester was compared to 778 non-exposed pregnancies. In the diclofenac exposed cohort 4 major birth defects were observed among 220 live-born infants and 25 spontaneous abortions occurred. Neither the rate of major birth defects (1.8% vs. 3.1%; OR adjusted 0.59; 95% CI 0.17-2.08) nor the risk of spontaneous abortion (HR adjusted 0.90; 95% CI 0.56-1.46) was increased. The study results do not indicate that diclofenac exposure during first trimester is associated with a teratogenic risk.

Exposure to cox-2 inhibitors (coxibs) during the first trimester and pregnancy outcome: a prospective observational cohort study.

PURPOSE: Cox-2-inhibitors (coxibs) are not recommended in pregnancy but early exposure may occur, for instance in unplanned pregnancies. Experience in pregnancy is limited leading to concerns in patients and their health care providers. Therefore, further data on coxibs and their effects on embryogenesis are needed. METHODS: This observational cohort study evaluates pregnancies ascertained in Germany during the study period from January 2000 to January 2016. A cohort of 174 women exposed to coxibs in the first trimester was compared to a randomly selected cohort of 521 women without exposure to coxibs, other nonsteroidal anti-inflammatory drugs or known teratogens. RESULTS: The overall rate of major birth defects was not significantly increased in the study cohort (2.9 vs. 2.7%, OR 1.08, 95% CI 0.34-3.42; OR adjusted 0.96, 95% CI 0.28-3.26). The cumulative incidence of spontaneous abortions was nonsignificantly lower in the exposed cohort (14.3 vs. 20.0%; HR, 0.90, 95% CI 0.51-1.58; HR adjusted, 0.87; 95% CI, 0.49-1.56). Elective terminations of pregnancies (ETOP), mainly for 'social' reasons, were more frequent in the coxib cohort (17.5 vs. 7.0%, HR, 2.31; 95% CI, 1.26-4.24; HR adjusted 2.12, 95% CI 1.13-3.97). CONCLUSIONS: Our study results support the assumption that coxibs are not major teratogens. Considering the still limited evidence basis on coxib exposure during pregnancy, well-established alternatives should be preferred.

Metamizole use during first trimester-A prospective observational cohort study on pregnancy outcome.

INTRODUCTION: The analgesic metamizole (dipyrone) is not recommended during pregnancy due to limited experience. In several countries, metamizole has no market authorization because of agranulocytosis as a rare but severe adverse effect. However, in others, metamizole is available and widely used as a pain reliever, and its use occurs also during pregnancy, often followed by fears of potential teratogenic risk. METHODS: This prospective observational cohort study compared pregnancy outcomes of 446 women exposed with metamizole in the first trimester with a randomly selected control cohort comprising 887 women not exposed to metamizole. Relevant data were obtained via structured questionnaires applied during the first trimester and 2 months after the expected date of birth between January 2000 and December 2015. RESULTS: The rate of major birth defects (7/373, 1.9%) was not increased in the metamizole cohort (OR adjusted 1.15, 95% CI 0.4-3.5). The cumulative incidences for spontaneous abortions did not reveal a significant difference between the exposed (12.2%, 32/446) and comparison cohort (19.4%, 77/887) (HR adjusted 0.72, 95% CI 0.5-1.1). Elective terminations of pregnancy (ETOP), mostly for "social" reasons, were more frequent in the metamizole (12.5%, 45/446) than in the comparison cohort (9.4%, 50/887; HR adjusted 1.48, 95% CI 0.98-2.2). CONCLUSIONS: Metamizole exposure in the first trimester does not seem to bear a substantial teratogenic risk. Our study results support reassurance in those instances where metamizole has been used during an unrecognized pregnancy or where its use appears indispensable.

Leflunomide - A human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database.

The teratogenic potential of leflunomide (LEF) in humans is still a matter of debate. We evaluated exposed pregnancies of our German Embryotox pharmacovigilance database. Inclusion criteria were LEF exposure anytime between 2 years before and 10 weeks after conception and no wash-out therapy before pregnancy. Of 65 prospectively enrolled pregnancies 47 were exposed during the 1st trimester and 18 preconceptional. Wash-out therapy was confirmed in 25 pregnancies. There were 10 spontaneous abortions and 19 elective terminations. Among 39 live-born children (including twins) one major malformation was recorded. A separate analysis of our retrospective adverse drug reaction database revealed one LEF-exposed case having no malformations. Our findings provide further evidence that LEF is not a major human teratogen. However, an embryotoxic potential resulting in an increased miscarriage rate cannot be ruled out. The recommendation of a waiting period of two years and a plasma level below 0.02mg/L seems too cautious.