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  • 101.
    Kilander, Helena
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Eksjo Nassjo Hospital, Sweden.
    Salomonsson, Birgitta
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Johan
    Jönköping University, Sweden.
    Brynhildsen, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Alehagen, Siw
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Contraceptive counselling of women seeking abortion - a qualitative interview study of health professionals experiences2017In: European journal of contraception & reproductive health care, ISSN 1362-5187, E-ISSN 1473-0782, Vol. 22, no 1Article in journal (Refereed)
    Abstract [en]

    Objectives: A substantial proportion of women who undergo an abortion continue afterwards without switching to more effective contraceptive use. Many subsequently have repeat unintended pregnancies. This study, therefore, aimed to identify and describe health professionalg experiences of providing contraceptive counselling to women seeking an abortion. Methods: We interviewed 21 health professionals (HPs), involved in contraceptive counselling of women seeking abortion at three differently sized hospitals in Sweden. The interviews were recorded and transcribed verbatim and analysed using conventional qualitative content analysis. Results: Three clusters were identified: Complex counselling, Elements of counselling and Finding a method. HPs often experienced consultations including contraceptive counselling at the time of an abortion as complex, covering both pregnancy termination and contraceptive counselling. Women with vulnerabilities placed even greater demands on the HPs providing counselling. The HPs varied in their approaches when providing contraceptive counselling but also in their knowledge about certain contraception methods. HPs described challenges in finding out if women had found an effective method and in the practicalities of arranging intrauterine device (IUD) insertion post-abortion, when a woman asked for this method. Conclusions: HPs found it challenging to provide contraceptive counselling at the time of an abortion and to arrange access to IUDs post-abortion. There is a need to improve their counselling, their skills and their knowledge to prevent repeat unintended pregnancies.

  • 102.
    Kindgren, Erik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Vastervik Hospital, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Early feeding and risk of Juvenile idiopathic arthritis: a case control study in a prospective birth cohort2017In: Pediatric Rheumatology, ISSN 1546-0096, E-ISSN 1546-0096, Vol. 15, article id 46Article in journal (Refereed)
    Abstract [en]

    Background: Juvenile idiopathic arthritis (JIA) is considered to be an autoimmune disease, but the etiology is unknown. We decided to study the influence of early nutrition on later development of JIA. Methods: All parents with children born between October 1, 1997 and October 1, 1999 in Southeast Sweden were asked to participate in the ABIS prospective cohort study (All Babies in Southeast Sweden), At 1 year, questionnaires with information on breastfeeding and introduction of foods were completed by 10,565 families. We identified 32 children with JIA and 111 children with non-chronic arthritis with completed questionnaires after delivery and after 1 year. A multivariable logistic regression model, adjusted for relevant factors, was performed to calculate the association between JIA and feeding during the first year of life. Results: An increased risk for JIA was found in children who had breast fed for less than 4 months, as opposed to those who were continued on breast milk beyond 4 months of age (aOR 3.5, 95% CI 1.4-8,5; p = 0.006). A short duration of exclusive as well as total breastfeeding was associated with an increased risk of JIA (aOR 1.3, 95% CI 1.1-1.6; p = 0.008 and aOR 1.2, 95% CI 1.1-1.3; p amp;lt; 0.001). All associations between breastfeeding and JIA persisted after adjustment. There was no relationship between early nutrition and non-chronic arthritis. Conclusions: Our results indicate that there are different disease mechanisms for different types of arthritis in childhood. Longer duration of breastfeeding (both total and exclusive) may protect against development of JIA. Mothers should be encouraged to breast-feed their babies exclusively, if at all possible, for 4 months and continue partial breastfeeding for an extended time when foreign proteins are introduced.

  • 103.
    Kindgren, Erik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Vastervik Hosp, Sweden; Skaraborg Hosp, Sweden.
    Guerrero Bosagna, Carlos
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Heavy metals in fish and its association with autoimmunity in the development of juvenile idiopathic arthritis: a prospective birth cohort study2019In: Pediatric Rheumatology, ISSN 1546-0096, E-ISSN 1546-0096, Vol. 17, article id 33Article in journal (Refereed)
    Abstract [en]

    BackgroundThe etiology of Juvenile Idiopathic Arthritis (JIA) is poorly understood. The purpose of this study was to examine the possible influence of early nutrition on later development of JIA.MethodsIn a population-based prospective birth cohort of 15,740 children we collected nutritional data, including fish consumption, and biological samples during pregnancy, at birth and at different ages. 16years after study inclusion we identified 42 children with JIA, of whom 11 were positive for Antinuclear Antibodies (ANA). Heavy metals were analysed in cord blood of all 42 JIA patients and 40 age and sex-matched controls. A multivariable logistic regression model, adjusted for relevant factors, was used as well as Mann-Whitney U-test.ResultsFish consumption more than once a week during pregnancy as well as during the childs first year of life was associated with an increased risk of JIA (aOR 4.5 (1.95-10.4); pamp;lt;0.001 and aOR 5.1 (2.1-12.4) pamp;lt;0.001) and of ANA-positivity (aOR 2.2 (1.4-3.6); p=0.002 and pamp;lt;0.001). Concentrations of Al, Cd, Hg and Li in cord blood were significantly higher in the JIA-group than in controls. The ANA-positive, all of whom had consumed fish amp;gt;once/week their first year, had significantly higher concentrations of Al (pamp;lt;0.001), Cd (p=0.003), and Li (pamp;lt;0.001) in cord blood than controls. Frequency of fish consumption correlated with concentrations of Cd (p=0.003), Li (p=0.015) and Hg (p=0.011).ConclusionsModerate exposure to heavy metals, associated with fish consumption, during pregnancy and early childhood may cause effects on the immune system of the offspring, resulting in ANA positivity and JIA.

  • 104.
    Kjölhede, Preben
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Bergdahl, Olga
    Region Östergötland.
    Borendal Wodlin, Ninnie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nilsson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Effect of intrathecal morphine and epidural analgesia on postoperative recovery after abdominal surgery for gynecologic malignancy: an open-label randomised trial2019In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, no 3, article id e024484Article in journal (Refereed)
    Abstract [en]

    Objectives We aimed to determine whether regional analgesia with intrathecal morphine (ITM) in an enhanced recovery programme (enhanced recovery after surgery [ERAS]) gives a shorter hospital stay with good pain relief and equal health-related quality of life (QoL) to epidural analgesia (EDA) in women after midline laparotomy for proven or assumed gynaecological malignancies. Design An open-label, randomised, single-centre study. Setting A tertiary referral Swedish university hospital. Participants Eighty women, 18-70 years of age, American Society of Anesthesiologists I and II, admitted consecutively to the department of Obstetrics and Gynaecology. Interventions The women were allocated (1: 1) to either the standard analgesic method at the clinic (EDA) or the experimental treatment (ITM). An ERAS protocol with standardised perioperative routines and standardised general anaesthesia were applied. The EDA or ITM started immediately preoperatively. The ITM group received morphine, clonidine and bupivacaine intrathecally; the EDA group had an epidural infusion of bupivacaine, adrenalin and fentanyl. Primary and secondary outcome measures Primary endpoint was length of hospital stay (LOS). Secondary endpoints were QoL and pain assessments. Results LOS was statistically significantly shorter for the ITM group compared with the EDA group (median [IQR] 3.3 [1.5-56.3] vs 4.3 [2.2-43.2] days; p=0.01). No differences were observed in pain assessment or QoL. The ITM group used postoperatively the first week significantly less opioids than the EDA group (median (IQR) 20 mg (14-35 mg) vs 81 mg (67-101 mg); pamp;lt;0.0001). No serious adverse events were attributed to ITM or EDA. Conclusions Compared with EDA, ITM is simpler to administer and manage, is associated with shorter hospital stay and reduces opioid consumption postoperatively with an equally good QoL. ITM is effective as postoperative analgesia in gynaecological cancer surgery.

  • 105.
    Klabbers, Gert A.
    et al.
    Tilburg Univ, Netherlands.
    Wijma, Klaas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Paarlberg, K. Marieke
    Gelre Hosp, Netherlands.
    Emons, Wilco H. M.
    Tilburg Univ, Netherlands.
    Vingerhoets, Ad J. J. M.
    Tilburg Univ, Netherlands.
    Haptotherapy as a new intervention for treating fear of childbirth: a randomized controlled trial2019In: Journal of Psychosomatic Obstetrics and Gynaecology, ISSN 0167-482X, E-ISSN 1743-8942, Vol. 40, no 1, p. 38-47Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate the effect of haptotherapy on severe fear of childbirth in pregnant women.Design: Randomized controlled trial.Setting: Community midwifery practices and a teaching hospital in the Netherlands.Population or Sample: Primi- and multigravida, suffering from severe fear of childbirth (N=134).Methods: Haptotherapy, psycho-education via Internet and care as usual were randomly assigned at 20-24weeks of gestation and the effects were compared at 36weeks of gestation and 6weeks and 6months postpartum. Repeated measurements ANOVA were carried out on the basis of intention to treat. Since there were crossovers from psycho-education via Internet and care as usual to haptotherapy, the analysis was repeated according to the as treated principle.Main outcome measures: Fear of childbirth score at the Wijma Delivery Expectancy/Experience Questionnaire.Results: In the intention to treat analysis, only the haptotherapy group showed a significant decrease of fear of childbirth, F(2,99)=3.321, p=.040. In the as treated analysis, the haptotherapy group showed a greater reduction in fear of childbirth than the other two groups, F(3,83)=6.717, pamp;lt;.001.Conclusion: Haptotherapy appears to be more effective in reducing fear of childbirth than psycho-education via Internet and care as usual.

  • 106.
    Klingberg, S.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. University of Gothenburg, Gothenburg, Sweden.
    Mehlig, K.
    Univ Gothenburg, Sweden.
    Sundh, V.
    Univ Gothenburg, Sweden.
    Heitmann, B. L.
    Parker Inst, Denmark; Bispebjerg and Fredriksberg Hosp, Denmark; Univ Southern Denmark, Denmark; Univ Copenhagen, Denmark.
    Lissner, L.
    Univ Gothenburg, Sweden.
    Lower risk of hip fractures among Swedish women with large hips?2018In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 29, no 4, p. 927-935Article in journal (Refereed)
    Abstract [en]

    In women, a large hip circumference (HC) related to lower hip fracture risk, independent of age and regardless if HC was measured long before or closer to the fracture. In older women, body mass index (BMI) explained the protection. In postmenopausal women, HC has been suggested to inversely associate with hip fracture while this has not been investigated in middle-aged women. We examined the association between HC, measured at two different time points, and hip fracture in a Swedish female population-based sample monitored for incident hip fractures over many years. Baseline HC, measured in 1968 or 1974 (n = 1451, mean age 47.6 years), or the HC measures that were the most proximal before event or censoring (n = 1325, mean age 71.7 years), were used to assess the effects of HC on hip fracture risk in women participating in the Prospective Population Study of Women in Gothenburg. HC was parameterized as quintiles with the lowest quintile (Q1) as reference. Incident hip fractures over 45 years of follow-up (n = 257) were identified through hospital registers. Higher quintiles of HC at both baseline and proximal to event were inversely associated with hip fracture risk in age-adjusted models, but only baseline HC predicted hip fractures independently of BMI and other covariates (HR (95% CI) Q2, 0.85 (0.56-1.27); Q3, 0.59 (0.36-0.96); Q4, 0.57 (0.34-0.96); Q5, 0.58 (0.31-1.10)). A large HC is protective against hip fracture in midlife and in advanced age, but the association between proximal HC and hip fracture was explained by concurrent BMI suggesting that padding was not the main mechanism for the association. The independent protection seen in middle-aged women points to other mechanisms influencing bone strength.

  • 107.
    Klingberg, Sofia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Department of Public Health and Community Medicine, Section for Epidemiology and Social Medicine (EPSO), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Brekke, Hilde K.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Introduction of fish and other foods during infancy and risk of asthma in the All Babies In Southeast Sweden cohort study2019In: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076, Vol. 178, no 3, p. 395-402Article in journal (Refereed)
    Abstract [en]

    The etiology of asthma includes lifestyle factors. Breastfeeding and introduction of complementary foods have been suggested to affect asthma risk, but the scientific foundation is not solid. Children from the birth cohort All Babies In Southeast Sweden study were included (n=9727). Breastfeeding duration and timing of introduction of infant formula and food were collected prospectively during the first year. Through linkage to the Swedish Patient Register, 948 children were identified with any asthma until age 15-17years, of which 450 cases were atopic. Breastfeeding duration was not associated to risk of asthma. Introduction of infant formula earlier than at 14weeks of age was associated with higher risk of non-atopic asthma. Introduction of fish before 43weeks of age, as compared to later, was associated with a lower risk of asthma, irrespective of atopic classification. Reverse causation was accounted for but did not explain the results.Conclusion: Introduction of infant formula and timing of introduction of fish seem to impact the long-term risk of doctor-diagnosed asthma. Emphasis on the growing body of evidence that early introduction of allergens offers protection against atopic disease should be considered in future recommendations.

  • 108.
    Klingberg, Sofia
    et al.
    Department of Public Health and Community Medicine, Section for Epidemiology and Social Medicine (EPSO), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, PO Box 454, 405 30 Gothenburg, Sweden.
    Ludvigsson, Johnny
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Brekke, Hilde K
    Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Introduction of complementary foods in Sweden and impact of maternal education on feeding practices.2017In: Public Health Nutrition, ISSN 1368-9800, E-ISSN 1475-2727, Vol. 20, no 6, p. 1054-1062Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe the introduction of complementary foods in a population-based cohort in relation to recommendations and explore the possible impact of maternal education on infant feeding practices.

    DESIGN: Prospective data from the All Babies in Southeast Sweden (ABIS) cohort study were used. The ABIS study invited all infants born in south-east Sweden during October 1997-October 1999 (n 21 700) to participate. A questionnaire was completed for 16 022 infants. During the infants' first year parents continuously filed in a diary covering introduction of foods.

    SETTING: Sweden.

    SUBJECTS: Infants (n 9727) with completed food diaries.

    RESULTS: Potatoes, vegetables, fruits/berries and porridge were the foods first introduced, with a median introduction between 19 and 22 weeks, followed by introduction of meat, cow's milk, follow-on formula and sour milk/yoghurt between 24 and 27 weeks. Early introduction of any food, before 16 weeks, occurred for 27 % of the infants and was more common in infants of mothers with low education. Overall, potatoes (14·7 %), vegetables (11·1 %), fruits/berries (8·5 %), porridge (7·4 %) and follow-on formula (2·7 %) were the foods most frequently introduced early. The majority of infants (≥70 %) were introduced to potatoes, vegetables, fruits/berries and porridge during concurrent breast-feeding, but introduction during concurrent breast-feeding was less common in infants of mothers with low education.

    CONCLUSIONS: Most infants were introduced to complementary foods timely in relation to recommendations. Low maternal education was associated with earlier introduction of complementary foods and less introduction during concurrent breast-feeding. Still, the results indicated exposure to fewer foods at 12 months in infants of mothers with low education.

  • 109.
    Knip, Mikael
    et al.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Akerblom, Hans K.
    University of Helsinki, Finland.
    Al Taji, Eva
    Charles University of Prague, Czech Republic.
    Becker, Dorothy
    University of Pittsburgh, PA USA.
    Bruining, Jan
    Sophia Childrens University Hospital, Netherlands.
    Castano, Luis
    University of Basque Country, Spain.
    Danne, Thomas
    Kinder-und Jugendkrankenhaus–Auf der Bult, Hannover, Germany.
    de Beaufort, Carine
    Centre Hospital Luxembourg, Luxembourg.
    Dosch, Hans-Michael
    University of Toronto, Canada.
    Dupre, John
    University of Western Ontario, Canada.
    Fraser, William D.
    University of Sherbrooke, Canada.
    Howard, Neville
    Childrens Hospital Westmead, Australia.
    Ilonen, Jorma
    University of Turku, Finland; Turku University Hospital, Finland.
    Konrad, Daniel
    Kinder and Jugendkrankenhaus Auf Der Bult, Germany; University of Childrens Hospital Zurich, Switzerland.
    Kordonouri, Olga
    Kinder and Jugendkrankenhaus Auf Der Bult, Germany.
    Krischer, Jeffrey P.
    University of S Florida, FL USA.
    Lawson, Margaret L.
    Childrens Hospital Eastern Ontario, Canada.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Madacsy, Laszlo
    Semmelweis University, Hungary.
    Mahon, Jeffrey L.
    University of Western Ontario, Canada.
    Ormisson, Anne
    Tartu University, Estonia.
    Palmer, Jerry P.
    University of Washington, WA USA.
    Pozzilli, Paolo
    University of Campus Biomed Rome, Italy.
    Savilahti, Erkki
    University of Helsinki, Finland.
    Serrano-Rios, Manuel
    CIBERDEM, Spain.
    Songini, Marco
    St Michelle Hospital, Italy.
    Taback, Shayne
    University of Manitoba, Canada.
    Vaarala, Outi
    University of Helsinki, Finland; AstraZeneca, Sweden.
    White, Neil H.
    Washington University, MO USA.
    Virtanen, Suvi M.
    National Institute Health and Welf, Finland.
    Wasikowa, Renata
    Medical Academic Wroclaw, Poland.
    Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes The TRIGR Randomized Clinical Trial2018In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 319, no 1, p. 38-48Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. OBJECTIVE To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. DESIGN, SETTING, AND PARTICIPANTS An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. INTERVENTIONS The participants received either a casein hydrolysate or a conventional adapted cows milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. MAIN OUTCOMES AND MEASURES Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). RESULTS Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8%[95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). CONCLUSIONS AND RELEVANCE Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes.

  • 110.
    Kurien, M.
    et al.
    Univ Sheffield, England.
    Ludvigsson, J. F.
    Karolinska Inst, Sweden; Orebro Univ, Sweden.
    Sanders, D. S.
    Univ Sheffield, England.
    Zylberberg, H. M.
    Columbia Univ Coll Phys and Surg, NY 10032 USA.
    Green, P. H.
    Columbia Univ Coll Phys and Surg, NY 10032 USA.
    Sundelin, Heléne
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Lebwohl, B.
    Karolinska Inst, Sweden; Columbia Univ Coll Phys and Surg, NY 10032 USA.
    Persistent mucosal damage and risk of epilepsy in people with celiac disease2018In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 25, no 3, p. 592-+Article in journal (Refereed)
    Abstract [en]

    Background and purposeCeliac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy. The objective of this study was to determine whether persistent VA on follow-up biopsy affected long-term epilepsy risk and epilepsy-related hospital emergency admissions. MethodsThis was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures. ResultsVillous atrophy was present in 43% of 7590 people with CD who had a follow-up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38-0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09-1.09). ConclusionsIn a population-based study of individuals with CD, persisting VA on follow-up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.

  • 111.
    Kvernebo-Sunnergren, Kjersti
    et al.
    Ryhov Cty Hosp, Sweden; Univ Gothenburg, Sweden.
    Ankarberg-Lindgren, Carina
    Univ Gothenburg, Sweden.
    Åkesson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Andersson, Mats X.
    Univ Gothenburg, Sweden.
    Samuelsson, Lena
    Sahlgrens Univ Hosp, Sweden.
    Lovmar, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Dahlgren, Jovanna
    Univ Gothenburg, Sweden.
    Hyperestrogenism Affects Adult Height Outcome in Growth Hormone Treated Boys With Silver-Russell Syndrome2018In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 780Article in journal (Refereed)
    Abstract [en]

    Background: Intrauterine growth retardation and short stature are common features in Silver-Russell syndrome (SRS). Despite recombinant growth hormone (rGH) treatment, poor pubertal height gain, affecting adult height (AH), is common. This study investigated whether growth patterns and estrogen concentrations are associated with AH outcome in rGH treated SRS males. Methods: In this retrospective longitudinal single-center study, 11 males with SRS were classified as non-responders (NR = 6) or responders (R = 5), depending on AH adjusted for midparental height. Epigenetic analysis and longitudinal growth measures, including bone age, rGH related parameters, pubertal development, gonadotropins and estrogen concentrations, were analyzed until AH. Results: Pubarche before 9 years was only observed in one NR. At 10 years of age, there was no difference in gonadotropins between NR and R. However, estradiol (E2) concentrations at 10 years of age showed a strong association to AH adjusted for MPH (r = -0.78, p amp;lt; 0.001). Serum E2 (pmol/L) was significantly higher in NR at ages 10 years [median (range) 2 (amp;lt;2-5) vs. amp;lt;2 (amp;lt;2)], 12 years [23 (10-57) vs. 2 (amp;lt;2-2)] and 14 years [77 (54-87) vs. 24 (amp;lt;2-38)] but not at 16 years. Birth weight standard deviation score (SDS) was lower in NR [-4.1 (-4.7 to -2.1) vs. -2.7 (-3.3 to -1.7)]. Weight gain (SDS) until pubertal onset was greater in NR [2.4 (1.4-3.5) vs. 0.8 (-0.4 to 1.7)] and pubertal height gain (SDS) was lower in NR [-1.0 (-2.7-0.4) vs. 0.1 (-0.1 to 1.1)]. At AH, a number of NR and R had high E2 concentrations and small testes. Conclusion: Increased E2 concentrations at age 10, 12, and 14 years were associated to less pubertal height gain, thus affecting AH. Due to the small number of patients, the results need to be confirmed in larger cohorts. The finding of impaired testicular development stresses the need of hormonal evaluation as a complement to clinical and radiological assessment when predicting AH in males with SRS.

  • 112.
    Lagergren, Katarina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nedstrand, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    The prevalence of primary ovarian insufficiency in Sweden; a national register study2018In: BMC Women's Health, ISSN 1472-6874, E-ISSN 1472-6874, Vol. 18, article id 175Article in journal (Refereed)
    Abstract [en]

    BackgroundThe current estimates of the prevalence of primary ovarian insufficiency (POI) are very variable, but are in most studies believed to be around 1%. It is also very likely tat the prevalence of POI differs between countries and over time. We therefore aimed to assess the prevalence of primary ovarian insufficiency in Sweden.MethodsAll 1,036,918 women born between 1973 and 1993 in Sweden were included. The prevalence of POI was based on data from the Swedish Patient Register through the diagnosis code or through the Prescribed Drug Register. The number of women below 40years of age diagnosed with the ICD-10 diagnoses E28.3 or E89.4, and women who had been dispensed drugs for treatment of climacteric symptoms were included.ResultsOut of the 1,036,918 women, 19,253 (1.9%) had POI. The prevalence of spontaneous POI was 1.7% and the prevalence of iatrogenic POI was 0.2%. Most women (98.8%) with POI were identified from the Prescribed Drug Register; only 4.1% were found in the Patient Register, whereas 2.9% were identified in both registers.ConclusionsThe total prevalence of POI was 1.9%, 95% CI: 1.7-2.1, indicating a higher prevalence than often previously reported.

  • 113.
    Lamont, Ronald F.
    et al.
    UCL, England; University of Southern Denmark, Denmark.
    Keelan, Jeffrey A.
    University of Western Australia, Australia.
    Larsson, Per-Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Skaraborg Hosp, Dept Obstet and Gynecol, Skovde, Sweden.
    Jörgensen, Jan S.
    University of Southern Denmark, Denmark; Odense University Hospital, Denmark.
    The treatment of bacterial vaginosis in pregnancy with clindamycin to reduce the risk of infection-related preterm birth: a response to the Danish Society of Obstetrics and Gynecology guideline groups clinical recommendations2017In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 96, no 2, p. 139-143Article in journal (Other academic)
    Abstract [en]

    Preterm birth is the major cause of perinatal mortality and morbidity worldwide. Infection/inflammation is responsible for a significant percentage of preterm birth, particularly at early gestations. A recent clinical recommendation by a guidelines group of the Danish Society of Obstetrics and Gynecology advised against the use of clindamycin for the treatment of bacterial vaginosis in pregnancy to reduce the risk of spontaneous preterm birth based on lack of evidence of efficacy. We believe that the evidence for the use of clindamycin for this indication is robust and that this recommendation was reached erroneously on the basis of flawed inclusion criteria: the inclusion of an unpublished study with poorly diagnosed bacterial vaginosis and the exclusion of an important pivotal study on the use of clindamycin in early pregnancy for the prevention of preterm birth. Had these errors been corrected, the conclusions would have been different.

  • 114.
    Larsson, Anna
    et al.
    Lund Univ, Sweden.
    Ottosson, Peter
    Lund Univ, Sweden.
    Törnqvist, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Olhager, Elisabeth
    Lund Univ, Sweden.
    Body composition and growth in full-term small for gestational age and large for gestational age Swedish infants assessed with air displacement plethysmography at birth and at 3-4 months of age2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0207978Article in journal (Refereed)
    Abstract [en]

    Background Being born small for gestational age (SGA) or large for gestational age (LGA) has short and long term metabolic consequences. There is a growing interest in the extent to which body composition, both in the short and the long term, differs in infants born at the extremes of these birth weights. Methods Body composition in 25 SGA and 25 LGA infants were assessed during the first days of life and at 3-4 months of age using air displacement plethysmography. Results SGA infants had significantly lower body fat (%) at birth compared to LGA infants. SGA infants increased their body weight and length at a significantly higher rate between birth and 3-4 months than LGA infants. Fat mass (g) in SGA infants increased 23 times between birth and 3-4 months of age compared to 2.8 times for LGA infants. At 3-4 months of age LGA infants reached a threshold in body fat (%) while SGA infants were still gaining body fat (%). Conclusion Several significant differences have been identified between SGA and LGA infants, indicating that the effects of intrauterine life continues to play an important role in body composition and growth during the first 3-4 months of life.

  • 115.
    Larsson, Christina R.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
    Januszewski, Andrzej S.
    NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia; Department of Diabetes and Endocrinology, St Vincent’s Hospital Melbourne and University of Melbourne, Melbourne, Victoria, Australia.
    McGrath, Rachel T.
    Department of Diabetes, Endocrinology and Metabolism, Northern Clinical School, The University of Sydney, Royal North Shore Hospital, Sydney, New South Wales, Australia.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Keech, Anthony C.
    NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
    MacIsaac, Richard J.
    Department of Diabetes and Endocrinology, St Vincent’s Hospital Melbourne and University of Melbourne, Melbourne, Victoria, Australia; Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
    Ward, Glenn M.
    Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
    ONeal, David N.
    NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia; Department of Diabetes and Endocrinology, St Vincent’s Hospital Melbourne and University of Melbourne, Melbourne, Victoria, Australia; Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
    Fulcher, Gregory R.
    Department of Diabetes, Endocrinology and Metabolism, Northern Clinical School, The University of Sydney, Royal North Shore Hospital, Sydney, New South Wales, Australia.
    Jenkins, Alicia J.
    NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia; Department of Diabetes and Endocrinology, St Vincent’s Hospital Melbourne and University of Melbourne, Melbourne, Victoria, Australia; Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
    Suboptimal behaviour and knowledge regarding overnight glycaemia in adults with type 1 diabetes is common2018In: Internal medicine journal (Print), ISSN 1444-0903, E-ISSN 1445-5994, Vol. 48, no 9, p. 1080-1086Article in journal (Refereed)
    Abstract [en]

    Background

    In people with type 1 diabetes (T1D), nocturnal hypoglycaemia (NH) can be slept through and can cause seizures, arrhythmias and death. Hypoglycaemia avoidance can induce hyperglycaemia and ketosis. Patient behaviour impacts clinical outcomes and may be changed by education.

    Aim

    To develop and utilise a survey to evaluate patient self‐management of overnight glycaemia in adults with T1D.

    Methods

    Adults with T1D attending two Australian tertiary referral diabetes clinics completed a survey about their diabetes self‐management and glycaemic control, including responses to hypothetical pre‐bed blood glucose (BG) levels (4–20 mmol/L). Statistical analyses included t‐tests, Chi square tests and ANOVA with significance considered at P < 0.05.

    Results

    There were 205 participants (103 females), with a mean (SD) age of 41 (17) years, T1D duration of 20 (16) years, HbA1c of 7.8(1.4)%, (61.3(8.2) mmol/mol), 38% on insulin pump therapy (CSII) and 36% with impaired hypoglycaemia awareness (IHA). Mean (SD) number of BG tests/day was 5.4 (2.7). Patients set higher BG target levels at bedtime and overnight: 7.5(1.4) and 7.1(1.3) mmol/L, respectively, compared to daytime (6.9(1.0); P < 0.0001 and P = 0.002 respectively). Only 36% of participants reported treating nocturnal hypoglycaemia (NH) with the recommended refined, then complex, carbohydrate. Only 28% of patients made safe choices in all bedtime BG scenarios, with higher rates for CSII users, P = 0.0005. Further education was desired by 32% of respondents, with higher rates in those with (44%) versus without IHA (25%), P = 0.006.

    Conclusions

    Many adults with T1D have suboptimal knowledge and behaviour regarding overnight BG self‐management. A survey, piloted herein, may facilitate the identification of patients who could benefit from further education.

  • 116.
    Leijon, Ingemar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Ingemansson, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Nelson, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Samuelsson, Stefan
    Linköping University, Department of Behavioural Sciences and Learning, Education, Teaching and Learning. Linköping University, Faculty of Educational Sciences.
    Wadsby, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Children with a very low birthweight showed poorer reading skills at eight years of age but caught up in most areas by the age of 102018In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 107, no 11, p. 1937-1945Article in journal (Refereed)
    Abstract [en]

    AIM: We evaluated the development of reading skills in very low birthweight (VLBW) children and controls at 8-10 years of age.

    METHODS: This study was part of a longitudinal study of VLBW infants born between January 1998 and December 1999 in Sweden. We recruited 49 VLBW children and 44 sex and age-matched full-term controls when they started school at the age of seven and tested them using identical methods for decoding, rapid naming ability, reading comprehension, and spelling and cognitive skills at about eight and 10 years of age. Univariate analysis of variance was performed to assess the effects of VLBW on reading performance at each age and to evaluate the differences between the groups and ages.

    RESULTS: Very low birthweight children scored significantly lower in all domains of reading at 7.8 ± 0.3 years, but the performance gap had narrowed by 9.8 ± 0.3 years. Significant catch-up gains were found in phonological awareness, rapid naming ability and reading comprehension. The differences between the groups were minor at 10 years, when controlled for non-verbal cognition.

    CONCLUSION: Very low birthweight children demonstrated worse reading performance at eight years of age than term-born controls. The gap in reading skills between the groups had largely narrowed two years later.

  • 117.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Dynamic regulation of DNA methylation in human T-cell biology2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    T helper cells play a central role in orchestrating immune responses in humans. Upon encountering a foreign antigen, T helper cells are activated followed by a differentiation process where the cells are specialised to help combating the infection. Dysregulation of T helper cell activation, differentiation and function has been implicated in numerous diseases, including autoimmunity and cancer. Whereas gene-regulatory networks help drive T-cell differentiation, acquisition of stable cell states require heritable epigenetic signals, such as DNA methylation. Indeed, the establishment of DNA methylation patterns is a key part of appropriate T-cell differentiation but how this is regulated over time remains unknown. Methylation can be directly attached to cytosine residues in DNA to form 5-methylcytosine (5mC) but the removal of DNA methylation requires multiple enzymatic reactions, commonly initiated by the conversion into 5-hydroxymethylcytosine (5hmC), thus creating a highly complex regulatory system. This thesis aimed to investigate how DNA methylation is dynamically regulated during T-cell differentiation.

    To this end, we employed large-scale profiling techniques combining gene expression as well as genome-wide 5mC and 5hmC measurements to construct a time-series model of epigenetic regulation of differentiation. This revealed that early T-cell activation was accompanied by extensive genome-wide deposition of 5hmC which resulted in demethylation upon proliferation. Early DNA methylation remodelling through 5hmC was not only indicative of demethylation events during T-cell differentiation but also marked changes persisting longterm in memory T-cell subsets. These results suggest that priming of epigenetic landscapes in T-cells is initiated during early activation events, preceding any establishment of a stable lineage, which are then maintained throughout the cells lifespan. The regions undergoing remodelling were also highly enriched for genetic variants in autoimmune diseases which we show to be functional through disruption of protein binding. These variants could potentially disrupt gene-regulatory networks and the establishment of epigenetic priming, highlighting the complex interplay between genetic and epigenetic layers. In the course of this work, we discovered that a commonly used technique to study genome-wide DNA modifications, DNA immunoprecipitation (DIP)-seq, had a false discovery rate between 50-99% depending on the modification and cell type being assayed. This represented inherent technical errors related to the use of antibodies resulting in off-target binding of repetitive sequences lacking any DNA modifications. These sequences are common in mammalian genomes making robust detection of rare DNA modifications very difficult due to the high background signals. However, offtarget binding could easily be controlled for using a non-specific antibody control which greatly improved data quality and biological insight of the data. Although future studies are advised to use alternative methods where available, error correction is an acceptable alternative which will help fuel new discoveries through the removal of extensive background signals.

    Taken together, this thesis shows how integrative use of high-resolution epigenomic data can be used to study complex biological systems over time as well as how these techniques can be systematically characterised to identify and correct errors resulting in improved detection.

    List of papers
    1. 5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
    Open this publication in new window or tab >>5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
    Show others...
    2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 2, p. 559-570Article in journal (Refereed) Published
    Abstract [en]

    5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.

    Place, publisher, year, edition, pages
    CELL PRESS, 2016
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-131186 (URN)10.1016/j.celrep.2016.05.091 (DOI)000380262300025 ()27346350 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council; Ake Wibergs Foundation; Cancerfonden; Helmholtz Zentrum Munchen; Technische Universitat Munchen; Biotechnology and Biological Sciences Research Council (BBSRC); CEFIC; Medical Research Council (MRC)

    Available from: 2016-09-19 Created: 2016-09-12 Last updated: 2019-03-19
    2. A reassessment of DNA-immunoprecipitation-based genomic profiling
    Open this publication in new window or tab >>A reassessment of DNA-immunoprecipitation-based genomic profiling
    Show others...
    2018 (English)In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 15, no 7, p. 499-+Article in journal (Refereed) Published
    Abstract [en]

    DNA immunoprecipitation followed by sequencing (DIP-seq) is a common enrichment method for profiling DNA modifications in mammalian genomes. However, the results of independent DIP-seq studies often show considerable variation between profiles of the same genome and between profiles obtained by alternative methods. Here we show that these differences are primarily due to the intrinsic affinity of IgG for short unmodified DNA repeats. This pervasive experimental error accounts for 50-99% of regions identified as enriched for DNA modifications in DIP-seq data. Correction of this error profoundly altered DNA-modification profiles for numerous cell types, including mouse embryonic stem cells, and subsequently revealed novel associations among DNA modifications, chromatin modifications and biological processes. We conclude that both matched input and IgG controls are essential in order for the results of DIP-based assays to be interpreted correctly, and that complementary, non-antibody-based techniques should be used to validate DIP-based findings to avoid further misinterpretation of genome-wide profiling data.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2018
    National Category
    Bioinformatics and Systems Biology
    Identifiers
    urn:nbn:se:liu:diva-149867 (URN)10.1038/s41592-018-0038-7 (DOI)000437934800012 ()29941872 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [2015-03495, 2015-02575]; LiU-Cancer [2016-007]; Swedish Cancer Society [CAN 2017/625, CAN 2016/602]; Medical Research Council, UK [MC_PC_U127574433]

    Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2019-05-01
  • 118.
    Lentini, Antonio
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lagerwall, Cathrine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Mjoseng, Heidi K.
    Univ Edinburgh, Scotland.
    Douvlataniotis, Dimitrios Karolos
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Vogt, Hartmut
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Meehan, Richard R.
    Univ Edinburgh, Scotland.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    A reassessment of DNA-immunoprecipitation-based genomic profiling2018In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 15, no 7, p. 499-+Article in journal (Refereed)
    Abstract [en]

    DNA immunoprecipitation followed by sequencing (DIP-seq) is a common enrichment method for profiling DNA modifications in mammalian genomes. However, the results of independent DIP-seq studies often show considerable variation between profiles of the same genome and between profiles obtained by alternative methods. Here we show that these differences are primarily due to the intrinsic affinity of IgG for short unmodified DNA repeats. This pervasive experimental error accounts for 50-99% of regions identified as enriched for DNA modifications in DIP-seq data. Correction of this error profoundly altered DNA-modification profiles for numerous cell types, including mouse embryonic stem cells, and subsequently revealed novel associations among DNA modifications, chromatin modifications and biological processes. We conclude that both matched input and IgG controls are essential in order for the results of DIP-based assays to be interpreted correctly, and that complementary, non-antibody-based techniques should be used to validate DIP-based findings to avoid further misinterpretation of genome-wide profiling data.

  • 119.
    Lewis, Kate Marie
    et al.
    UCL, England.
    Ruiz, Milagros
    UCL, England.
    Goldblatt, Peter
    UCL, England.
    Morrison, Joana
    UCL, England.
    Porta, Daniela
    Lazio Regional Health Syst, Italy.
    Forastiere, Francesco
    Lazio Regional Health Syst, Italy.
    Hryhorczuk, Daniel
    University of Illinois, IL USA.
    Zvinchuk, Oleksandr
    National Academic Medical Science Ukraine, Ukraine.
    Saurel-Cubizolles, Marie-Josephe
    Paris Descartes University, France.
    Lioret, Sandrine
    Paris Descartes University, France.
    Annesi-Maesano, Isabella
    Pierre Louis Institute Epidemiol and Public Health iPLESP, France.
    Vrijheid, Martine
    ISGlobal, Spain; UPF, Spain; Spanish Consortium Research Epidemiol and Public Health CIBE, Spain.
    Torrent, Maties
    Spanish Consortium Research Epidemiol and Public Health CIBE, Spain; IB Salut Menorca Health Area, Spain.
    Iniguez, Carmen
    Spanish Consortium Research Epidemiol and Public Health CIBE, Spain; University of Valencia, Spain.
    Larranaga, Isabel
    Public Health Department Gipuzkoa, Spain; BIODONOSTIA Health Research Institute, Spain.
    Harskamp-van Ginkel, Margreet W.
    University of Amsterdam, Netherlands.
    Vrijkotte, Tanja G. M.
    University of Amsterdam, Netherlands.
    Klanova, Jana
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Svancara, Jan
    Masaryk University, Czech Republic.
    Barross, Henrique
    University of Porto, Portugal; University of Porto, Portugal.
    Correia, Sofia
    University of Porto, Portugal; University of Porto, Portugal.
    Jarvelin, Marjo-Riitta
    Imperial Coll London, England; University of Oulu, Finland; Oulu University Hospital, Finland; University of Oulu, Finland.
    Taanila, Anja
    University of Oulu, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Tomas
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Marmot, Michael
    UCL, England.
    Pikhart, Hynek
    UCL, England.
    Mothers education and offspring asthma risk in 10 European cohort studies2017In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 32, no 9, p. 797-805Article in journal (Refereed)
    Abstract [en]

    Highly prevalent and typically beginning in childhood, asthma is a burdensome disease, yet the risk factors for this condition are not clarified. To enhance understanding, this study assessed the cohort-specific and pooled risk of maternal education on asthma in children aged 3-8 across 10 European countries. Data on 47,099 children were obtained from prospective birth cohort studies across 10 European countries. We calculated cohort-specific prevalence difference in asthma outcomes using the relative index of inequality (RII) and slope index of inequality (SII). Results from all countries were pooled using random-effects meta-analysis procedures to obtain mean RII and SII scores at the European level. Final models were adjusted for child sex, smoking during pregnancy, parity, mothers age and ethnicity. The higher the score the greater the magnitude of relative (RII, reference 1) and absolute (SII, reference 0) inequity. The pooled RII estimate for asthma risk across all cohorts was 1.46 (95% CI 1.26, 1.71) and the pooled SII estimate was 1.90 (95% CI 0.26, 3.54). Of the countries examined, France, the United Kingdom and the Netherlands had the highest prevalences of childhood asthma and the largest inequity in asthma risk. Smaller inverse associations were noted for all other countries except Italy, which presented contradictory scores, but with small effect sizes. Tests for heterogeneity yielded significant results for SII scores. Overall, offspring of mothers with a low level of education had an increased relative and absolute risk of asthma compared to offspring of high-educated mothers.

  • 120.
    Li, Junwei
    et al.
    Univ Murcia, Spain.
    Barranco, Isabel
    Univ Murcia, Spain.
    Tvarijonaviciute, Asta
    Univ Murcia, Spain.
    Molina, Manuel F.
    Univ Murcia, Spain.
    Martinez, Emilio A.
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Parrilla, Inmaculada
    Univ Murcia, Spain.
    Roca, Jordi
    Univ Murcia, Spain.
    Seminal plasma antioxidants are directly involved in boar sperm cryotolerance2018In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 107, p. 27-35Article in journal (Refereed)
    Abstract [en]

    Boar ejaculates are ejected in fractions with a specific composition in terms of sperm numbers and seminal plasma (SP), which is reflected in the varying sperm cryotolerance observed among different fractions. As boar sperm are particularly sensitive to oxidative stress, this study evaluated the role of SP antioxidants in the observed differences in sperm cryotolerance among ejaculate fractions. Ten ejaculates from five boars were manually collected in fractions: the first 10 mL of the sperm-rich fraction (SRF), the rest of the SRF and the post-SRF. Semen samples comprising the entire ejaculate (EE) were created by proportionally mixing the three fractions described above. Each of the 40 resulting semen samples was split into two aliquots: one was used for sperm cryopreservation following a standard protocol utilizing 0.5-mL straws, and the other was used to collect SP for antioxidant assessment. Frozen-thawed (FT) sperm from the SRF (the first 10 mL of the SRF and the rest of the SRF) and those from post-SRF were of the highest and worst quality, respectively, which was measured in terms of total and objective progressive motility and viability (P amp;lt; 0.01). Viable FT sperm from the post-SRF generated more reactive oxygen species and experienced more lipid peroxidation than those from the SRF (both the first 10 mL and the rest of the SRF) (P amp;lt; 0.01). The percentage of FT sperm exhibiting fragmented nuclear DNA did not differ among ejaculate fractions and the EE. Catalase, glutathione peroxidase and glutathione peroxidase 5 (GPx-5) were lowest in SP from the first 10 mL of the SRF (P amp;lt; 0.001), whereas superoxide dismutase (SOD) and paraoxonase 1 (PON-1) were highest in SP of the SRF (both the first 10 mL and the rest of the SRF) (P amp;lt; 0.01). Trolox-equivalent antioxidant capacity (TEAC) and the ferric-reducing ability of plasma (FRAP) were highest in SP from the first 10 mL of the SRF and lowest in the post-SRF (P amp;lt; 0.001), whereas cupric-reducing antioxidant capacity was lowest (P amp;lt; 0.05) in SP from the first 10 mL of the SRF. Regression analyses indicated that certain SP antioxidants had good predictive value for post-thaw recovery rates of total motility (R-2 = 54.8%, P amp;lt; 0.001; including SOD, TEAC and FRAP) and viability (R-2 = 56.1%, P amp;lt; 0.001; including SOD, PON-1, GPx-5 and TEAC). These results demonstrated that certain SP antioxidants are positively involved in boar sperm cryotolerance, minimizing the oxidative stress imposed by cryogenic handling. (C) 2017 Elsevier Inc. All rights reserved.

  • 121.
    Li, Junwei
    et al.
    Univ Murcia, Spain.
    Parrilla, Inmaculada
    Univ Murcia, Spain.
    Ortega, Maria D.
    Univ Murcia, Spain.
    Martinez, Emilio A.
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Roca, Jordi
    Univ Murcia, Spain.
    Post-thaw boar sperm motility is affected by prolonged storage of sperm in liquid nitrogen. A retrospective study2018In: Cryobiology, ISSN 0011-2240, E-ISSN 1090-2392, Vol. 80, p. 119-125Article in journal (Refereed)
    Abstract [en]

    Owing to the quick genetic turnover of the pig industry, most AT-boar sires live 2-3 yr, a period during which for 1-2 yr their semen is extended and used in liquid form for AI. Despite showing low cryosurvival, affecting fertility after AI, boar semen is frozen for easiness of transport overseas and reposition of valuable genetics. For the latter, semen is stored in liquid nitrogen (LN2, cryostorage) for many years, a controversial practice. Here we studied how length of cryostorage could affect sperm quality. Straws (0.5 mL) frozen using the same cryopreservation protocol at one specific location from AI-sires of proven fertility were stored in LN2 for up to 8 yr. Post thaw sperm quality was evaluated after 2, 4 or 8 yr of cryostorage, always compared to early thawing (15 d after freezing). Sperm motility and kinematics were evaluated post-thaw using CASA and sperm viability was cytometrically evaluated using specific fluorophores. Sperm viability was not affected by length of cryostorage, but total and progressive sperm motility were lower (p amp;lt; 0.01) in sperm samples cryostored for 4 or 8 yr compared to those thawed 15 d after freezing. Cryostorage time affected sperm kinetics, but with greater intensity in the samples cryostored for 4 yr (p amp;lt; 0.001) than in those for 2 yr (p amp;lt; 0.01). The fact that the major phenotypic characteristic of boar spermatozoa, motility, is constrained by time of cryostorage should be considered when building cryobanks of pig semen. Attention should be placed on the finding that amp;gt; 2 yr of cryostorage time can be particularly detrimental for the post-thaw motility of some sires, which might require increasing sperm numbers for AI.

  • 122.
    Li, Junwei
    et al.
    Univ Murcia, Spain.
    Roca, Jordi
    Univ Murcia, Spain.
    Perez-Patino, Cristina
    Univ Murcia, Spain.
    Barranco, Isabel
    Univ Murcia, Spain.
    Martinez, Emilio A.
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Parrilla, Inmaculada
    Univ Murcia, Spain.
    Is boar sperm freezability more intrinsically linked to spermatozoa than to the surrounding seminal plasma?2018In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 195, p. 30-37Article in journal (Refereed)
    Abstract [en]

    This study aimed to elucidate the effect of seminal plasma (SP) from post-SRF on boar sperm freezability and, in addition, to determine the relevance of sperm itself to sustain cryopreservation, regardless of the SP surrounding them. Twelve ejaculates from three boars were manually collected in fractions/portions, P1: the first 10 mL of the SRF, P2: the rest of the SRF and the post-SRF. Immediately, samples were centrifuged to separate spermatozoa from the surrounding SP. Spermatozoa from P1 and P2 were then incubated with its own SP or that from post-SRF, diluted in BTS (1:1, v/v) at 17 degrees C overnight before being frozen in 0.5 mL straws using a standard protocol. Sperm motility (total and progressive) deteriorated (P amp;lt; 0.05) when P1- or P2-sperm when incubated overnight in SP from post-SRF, while sperm viability differed between P1 and P2 (P amp;lt; 0.05) regardless of the SP they were incubated in. Post-thaw sperm quality and functionality differed between P1 and P2, regardless of the SP used for overnight pre-freezing incubation. Post-thaw motility (P amp;lt; 0.05) and viability (P amp;lt; 0.01), as well as plasma membrane fluidity (P amp;lt; 0.05) or lipid peroxidation values (P amp;lt; 0.01) were best in P1 sperm compared to those of P2. The protein profile of sperm from P1 and P2, analyzed by 2D-PAGE, showed qualitative differences, which suggest that sperm rather than SP would explain differences in sperm freezability between ejaculate fractions/portions. Use of P1 fraction spermatozoa seems thus optimal for cryopreservation.

  • 123.
    Liffner, Susanne
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nedstrand, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Men becoming fathers by intracytoplasmic sperm injection were more often born small for gestational to age2017In: Asian Journal of Andrology, ISSN 1008-682X, E-ISSN 1745-7262, Vol. 19, no 1, p. 103-106Article in journal (Refereed)
    Abstract [en]

    Being born with nonoptimal birth characteristics decreases the chance of becoming a father. Urogenital malformations as well as metabolic syndrome are more common in men born small for gestational age (SGA) and could be contributing factors to the reduced fertility rate seen in these men. It could imply that men becoming fathers by assisted reproductive technology (ART) more often are born with low birth weight (LBW), preterm, and/or SGA than men conceiving without treatment and also that men where intracytoplasmic sperm injection (ICSI) had to be performed more often are born with nonoptimal birth characteristics than men where conventional in vitro fertilization (IVF) successfully could be used. In this retrospective, case-control study using Swedish national registers, we compared the birth characteristics of 1206 men who have become fathers by ART with a control group consisting of age-matched men who became fathers without treatment. The differences in birth characteristics between men becoming fathers by IVF and ICSI were also assessed. For men becoming fathers by ART, OR of being born with LBW was 1.66 (95% CI = 1.17-2.36) compared with fathers who conceived without treatment. OR of being born prematurely was 1.32 (95% CI = 1.00-1.77). Men becoming fathers via ICSI had a doubled increased likelihood of being born SGA compared with men who became fathers via IVF (OR = 2.12; 95% CI = 1.17-3.83). In conclusion, we have found that men becoming fathers by ICSI treatments had more often been born SGA than men becoming fathers by conventional IVF.

  • 124.
    Liffner, Susanne
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Pehrson, Isabelle
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Garcia-Calvo, Laura
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nedstrand, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Zalavary, Stefan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Alvarez-Rodriguez, Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Diagnostics of DNA fragmentation in human spermatozoa: Are sperm chromatin structure analysis and sperm chromatin dispersion tests (SCD-HaloSpermG2 (R)) comparable?2019In: Andrologia, ISSN 0303-4569, E-ISSN 1439-0272, Vol. 51, no 8, article id e13316Article in journal (Refereed)
    Abstract [en]

    Men affected with idiopathic infertility often display basic spermiogramme values similar to fertile individuals, questioning the diagnostic impact of the World Health Organization (WHO) thresholds used. This study explored sperm DNA fragmentation in single ejaculates from 14 fertile donors and 42 patients with idiopathic infertility providing semen for assisted reproductive techniques in a university fertility clinic. Each ejaculate was simultaneously studied for sperm DNA fragmentation by the flow cytometer-based sperm chromatin structure analysis (SCSA) and the new light-microscopy-based sperm chromatin dispersion assay (SCD-HaloSpermG2 (R)), before and after sperm selection for in vitro fertilisation with a colloid discontinuous gradient. The WHO semen variables did not differ between groups, but DNA fragmentation after SCSA (DFI) or SCD (SDF) was significantly (p amp;lt; 0.05) higher in patients (DFI: 40.2% +/- 3.0 vs. SDF: 40.3% +/- 1.4) than in fertile donors (DFI: 17.1% +/- 2.1 vs. SDF: 20.9% +/- 2.5). Sperm selection led to lower proportions of DNA-fragmented spermatozoa (DFI: 11.9 +/- 1.7 vs. SCD: 10.0 +/- 0.9, p amp;lt; 0.05). The techniques output correlated highly and significantly (r(2) = 0.82). DNA fragmentation is confirmed as a relevant variable for scrutinising patients with idiopathic infertility, beyond the evidently insufficient WHO semen analyses. Since both techniques yielded similar results, the reduced necessity of complex equipment when running SCD ought to be considered for a clinical setting.

    The full text will be freely available from 2020-05-17 10:44
  • 125.
    Lilliecreutz, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Cedergren, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Dags att implementera nya rön om graviditetsdiabetes2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Other academic)
    Abstract [en]

    n/a

  • 126.
    Lind, Marcus
    et al.
    Univ Gothenburg, Sweden; NU Hosp Grp, Sweden.
    Pivodic, Aldina
    Stat Konsultgrp, Sweden.
    Svensson, Ann-Marie
    Univ Gothenburg, Sweden; Ctr Registers Reg Vastra Gotaland, Sweden.
    Olafsdottir, Arndis F.
    Univ Gothenburg, Sweden; NU Hosp Grp, Sweden.
    Wedel, Hans
    Univ Gothenburg, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    HbA(1c) level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study2019In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 366, article id l4894Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To evaluate if the lowest target level for glycated haemoglobin (HbA(1c)) of amp;lt; 6.5% is associated with lower risk for retinopathy and nephropathy than less tight control in children and adults with type 1 diabetes. DESIGN Population based cohort study. SETTING Swedish National Diabetes Registry, 1 January 1998 to 31 December 2017. PARTICIPANTS 10 398 children and adults with type 1 diabetes followed from diagnosis, or close thereafter, until end of 2017. MAIN OUTCOME MEASURES Relative risk (odds ratios) for retinopathy and nephropathy for different mean levels of HbA(1c). RESULTS Mean age of participants was 14.7 years (43.4% female), mean duration of diabetes was 1.3 years, and mean HbA(1c) level was 8.0% (63.4 mmol/mol). After adjustment for age, sex, duration of diabetes, blood pressure, blood lipid levels, body mass index, and smoking, the odds ratio for mean HbA(1c) amp;lt; 6.5% (amp;lt; 48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol) for any retinopathy (simplex or worse) was 0.77 (95% confidence interval 0.56 to 1.05, P=0.10), for preproliferative diabetic retinopathy or worse was 3.29 (0.99 to 10.96, P=0.05), for proliferative diabetic retinopathy was 2.48 (0.71 to 8.62, P=0.15), for microalbuminuria or worse was 0.98 (0.60 to 1.61, P=0.95), and for macroalbuminuria was 2.47 (0.69 to 8.87, P=0.17). Compared with HbA(1c) levels 6.56.9%, HbA(1c) levels 7.0-7.4% (53-57 mmol/mol) were associated with an increased risk of any retinopathy (1.31, 1.05 to 1.64, P=0.02) and microalbuminuria (1.55, 1.03 to 2.32, P=0.03). The risk for proliferative retinopathy (5.98, 2.10 to 17.06, Pamp;lt;0.001) and macroalbuminuria (3.43, 1.14 to 10.26, P=0.03) increased at HbA(1c) levels amp;gt; 8.6% (amp;gt; 70 mmol/mol). The risk for severe hypoglycaemia was increased at mean HbA(1c) amp;lt; 6.5% compared with 6.5-6.9% (relative risk 1.34, 95% confidence interval 1.09 to 1.64, P=0.005). CONCLUSIONS Risk of retinopathy and nephropathy did not differ at HbA(1c) levels amp;lt; 6.5% but increased for severe hypoglycaemia compared with HbA(1c) levels 6.5-6.9%. The risk for severe complications mainly occurred at HbA(1c) levels amp;gt; 8.6%, but for milder complications was increased at HbA(1c) levels amp;gt; 7.0%.

  • 127.
    Lind, Tekla
    et al.
    Södersjukhuset, Sweden.
    Holte, Jan
    Carl von Linne Clin, Sweden; Uppsala Ctr Reprod Biol, Sweden.
    Olofsson, Jan I.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hadziosmanovic, Nermin
    Uppsala Univ, Sweden.
    Gudmundsson, Johannes
    Uppsala Univ Hosp, Sweden.
    Nedstrand, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Lood, Mikael
    Örebro Univ Hosp, Sweden.
    Berglund, Lars
    Uppsala Univ, Sweden.
    Rodriguez-Wallberg, Kenny
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Reduced live-birth rates after IVF/ICSI in women with previous unilateral oophorectomy: results of a multicentre cohort study2018In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 33, no 2, p. 238-247Article in journal (Refereed)
    Abstract [en]

    Is there a reduced live-birth rate (LBR) after IVF/ICSI treatment in women with a previous unilateral oophorectomy (UO)? A significantly reduced LBR after IVF/ICSI was found in women with previous UO when compared with women with intact ovaries in this large multicentre cohort, both crudely and after adjustment for age, BMI, fertility centre and calendar period and regardless of whether the analysis was based on transfer of embryos in the fresh cycle only or on cumulative results including transfers using frozen-thawed embryos. Similar pregnancy rates after IVF/ICSI have been previously reported in case-control studies and small cohort studies of women with previous UO versus women without ovarian surgery. In all previous studies multiple embryos were transferred. No study has previously evaluated LBR in a large cohort of women with a history of UO. This research was a multicentre cohort study, including five reproductive medicine centres in Sweden: Carl von Linn, Clinic (A), Karolinska University Hospital (B), Uppsala University Hospital (C), Linkoping University Hospital (D) and A-rebro University Hospital (E). The women underwent IVF/ICSI between January 1999 and November 2015. Single embryo transfer (SET) was performed in approximately 70% of all treatments, without any significant difference between UO exposed women versus controls (68% versus 71%), respectively (P = 0.32), and a maximum of two embryos were transferred in the remaining cases. The dataset included all consecutive treatments and fresh and frozen-thawed cycles. The exposed cohort included 154 women with UO who underwent 301 IVF/ICSI cycles and the unexposed control cohort consisted of 22 693 women who underwent 41 545 IVF/ICSI cycles. Overall, at the five centres (A-E), the exposed cohort underwent 151, 34, 35, 41 and 40 treatments, respectively, and they were compared with controls of the same centre (18 484, 8371, 5575, 4670 and 4445, respectively). The primary outcome was LBR, which was analysed per started cycle, per ovum pick-up (OPU) and per embryo transfer (ET). Secondary outcomes included the numbers of oocytes retrieved and supernumerary embryos obtained, the Ovarian Sensitivity Index (OSI), embryo quality scores and cumulative pregnancy rates. We used a Generalized Estimating Equation (GEE) model for statistical analysis in order to account for repeated treatments. MAIN RESULTS AND THE ROLE OF CHANCE: The exposed (UO) and control womens groups were comparable with regard to age and performance of IVF or ICSI. Significant differences in LBR, both crude and age-adjusted, were observed between the UO and control groups: LBR per started cycle (18.6% versus 25.4%, P = 0.007 and P = 0.014, respectively), LBR/OPU (20.3% versus 27.1%, P = 0.012 and P = 0.015, respectively) and LBR/ET (23.0% versus 29.7%, P = 0.022 and P = 0.025, respectively). The differences in LBR remained significant after inclusion of both fresh and frozen-thawed transfers (both crude and age-adjusted data): LBR/OPU (26.1% versus 34.4%, P = 0.005 and P = 0.006, respectively) and LBR/ET (28.3% versus 37.1%, P = 0.006 and P = 0.006, respectively). The crude cancellation rate was significantly higher among women with a history of UO than in controls (18.9% versus 14.5%, P = 0.034 and age-adjusted, P = 0.178). In a multivariate GEE model, the cumulative odds ratios for LBR (fresh and frozen-thawed)/OPU (OR 0.70, 95% CI 0.52-0.94, P = 0.016) and LBR (fresh and frozen-thawed)/ET (OR 0.68, 95% CI 0.51-0.92, P = 0.012) were approximately 30% lower in the group of women with UO when adjusted for age, BMI, reproductive centre, calendar period and number of embryos transferred when appropriate. The OSI was significantly lower in women with a history of UO than in controls (3.6 versus 6.0) and the difference was significant for both crude and age-adjusted data (P =amp;lt; 0.001 for both). Significantly fewer oocytes were retrieved in treatments of women with UO than in controls (7.2 versus 9.9, P = amp;lt; 0.001, respectively). LIMITATIONS, REASONS FOR CAUTION: Due to the nature of the topic, this is a retrospective analysis, with all its inherent limitations. Furthermore, the cause for UO was not possible to obtain in all cases. A diagnosis of endometriosis was also more common in the UO group, i. e. a selection bias in terms of poorer patient characteristics in the UO group cannot be completely ruled out. However, adjustment for all known confounders did not affect the general results. WIDER IMPLICATIONS OF THE FINDINGS: To date, this is the largest cohort investigated and the first study indicating an association of achieving reduced live birth after IVF/ICSI in women with previous UO. These findings are novel and contradict the earlier notion that IVF/ICSI treatment is not affected, or is only marginally affected by previous UO.

  • 128.
    Lindau, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Bhai Mehta, Ratnesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lash, G. E.
    Guangzhou Women and Childrens Med Ctr, Peoples R China.
    Papapavlou, Georgia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Svensson Arvelund, Judit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Interleukin-34 is present at the fetal-maternal interface and induces immunoregulatory macrophages of a decidual phenotype in vitro2018In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 33, no 4, p. 588-599Article in journal (Refereed)
    Abstract [en]

    STUDY QUESTION: Is the newly discovered cytokine interleukin (IL)-34 expressed at the human fetal-maternal interface in order to influence polarization of monocytes into macrophages of a decidual immunoregulatory phenotype? SUMMARY ANSWER: IL-34 was found to be present at the fetal-maternal interface, in both fetal placenta and maternal decidua, and it was able to polarize monocytes into macrophages of a decidual phenotype. WHAT IS KNOWN ALREADY: IL-34 was shown to bind to the same receptor as macrophage-colony stimulating factor (M-CSF), which has an important immunomodulatory role at the fetal-maternal interface, for example by polarizing decidual macrophages to an M2-like regulatory phenotype. IL-34 is known to regulate macrophage subsets, such as microglia and Langerhans cells, but its presence at the fetal-maternal interface is unknown. STUDY DESIGN, SIZE, DURATION: The presence of IL-34 at the fetal-maternal interface was evaluated by immunohistochemistry (IHC) and ELISA in placental and decidual tissues as well as in isolated trophoblast cells and decidual stromal cells obtained from first trimester elective surgical terminations of pregnancy (n = 49). IL-34 expression was also assessed in third trimester placental biopsies from women with (n = 21) or without (n = 15) pre-eclampsia. The effect of IL-34 on macrophage polarization was evaluated in an in vitro model of blood monocytes obtained from healthy volunteers (n = 14). In this model, granulocyte macrophage-colony stimulating factor (GM-CSF) serves as a growth factor for M1-like polarization, and M-CSF as a growth factor for M2-like polarization. PARTICIPANTS/MATERIALS, SETTING, METHODS: First trimester placental and decidual tissues were obtained from elective pregnancy terminations. Placental biopsies were obtained from women with pre-eclampsia and matched controls in the delivery ward. Polarization of macrophages in vitro was determined by flow-cytometric phenotyping and secretion of cytokines and chemokines in cell-free supernatants by multiplex bead assay. MAIN RESULTS AND THE ROLE OF CHANCE: Our study shows that IL-34 is produced at the fetal-maternal interface by both placental cyto-and syncytiotrophoblasts and decidual stromal cells. We also show that IL-34, in vitro, is able to polarize blood monocytes into macrophages with a phenotype (CD14(high)CD163(+)CD209(+)) and cytokine secretion pattern similar to that of decidual macrophages. The IL-34-induced phenotype was similar, but not identical to the phenotype induced by M-CSF, and both IL-34-and M-CSF-induced macrophages were significantly different (P amp;lt; 0.05-0.0001 depending on marker) from GM-CSF-polarized M1-like macrophages. Our findings suggest that IL-34 is involved in the establishment of the tolerant milieu found at the fetal-maternal interface by skewing polarization of macrophages into a regulatory phenotype. LIMITATIONS, REASONS FOR CAUTION: Although it is clear that IL-34 is present at the fetal-maternal interface and polarizes macrophages in vitro, its precise role in vivo remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The recently discovered cytokine IL-34 is present at the fetal-maternal interface and has immunomodulatory properties with regard to induction of decidual macrophages, which are important for a healthy pregnancy. Knowledge of growth factors related to macrophage polarization can potentially be translated to treatment of pregnancy complications involving dysregulation of this process. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by grants from the Medical Research Council (Grant K2013-61X-22310-01-04), the Research Council of South-East Sweden (FORSS), and the County Council of Ostergotland, Sweden. No author has any conflicts of interest to declare.

  • 129.
    Lindell, Nina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Carlsson, Annelie
    Lund University, Sweden.
    Josefsson, Ann
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Maternal obesity as a risk factor for early childhood type 1 diabetes: a nationwide, prospective, population-based case-control study2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 1, p. 130-137Article in journal (Refereed)
    Abstract [en]

    Genetic and environmental factors are believed to cause type 1 diabetes. The aim of this study was to investigate the influence of maternal BMI and gestational weight gain on the subsequent risk of childhood type 1 diabetes. Children in the Swedish National Quality Register for Diabetes in Children were matched with control children from the Swedish Medical Birth Register. Children were included whose mothers had data available on BMI in early pregnancy and gestational weight gain, giving a total of 16,179 individuals: 3231 children with type 1 diabetes and 12,948 control children. Mothers of children with type 1 diabetes were more likely to be obese (9% [n = 292/3231] vs 7.7% [n = 991/12,948]; p = 0.02) and/or have diabetes themselves (2.8% [n = 90/3231] vs 0.8% [n = 108/12,948]; p amp;lt; 0.001) compared with mothers of control children. Gestational weight gain did not differ significantly between the two groups of mothers. In mothers without diabetes, maternal obesity was a significant risk factor for type 1 diabetes in the offspring (p = 0.04). A child had an increased risk of developing type 1 diabetes if the mother had been obese in early pregnancy (crude OR 1.20; 95% CI 1.05, 1.38; adjusted OR 1.18; 95% CI 1.02, 1.36). Among children with type 1 diabetes (n = 3231) there was a difference (p amp;lt; 0.001) in age at onset in relation to the mothers BMI. Among children in the oldest age group (15-19 years), there were more mothers who had been underweight during pregnancy, while in the youngest age group (0-4 years) the pattern was reversed. Maternal obesity, in the absence of maternal diabetes, is a risk factor for type 1 diabetes in the offspring, and influences the age of onset of type 1 diabetes. This emphasises the importance of a normal maternal BMI to potentially decrease the incidence of type 1 diabetes.

  • 130.
    Lindh Falk, Annika
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy. Linköping University, Faculty of Medicine and Health Sciences.
    Hult, Håkan
    Karolinska Inst, Sweden.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Hopwood, Nick
    Univ Technol Sydney, Australia; Univ Stellenbosch, South Africa.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nursing assistants mattersAn ethnographic study of knowledge sharing in interprofessional practice2018In: Nursing Inquiry, ISSN 1320-7881, E-ISSN 1440-1800, Vol. 25, no 2, article id e12216Article in journal (Refereed)
    Abstract [en]

    Interprofessional collaboration involves some kind of knowledge sharing, which is essential and will be important in the future in regard to the opportunities and challenges in practices for delivering safe and effective health care. Nursing assistants are seldom mentioned as a group of health care workers that contribute to interprofessional collaboration in health care practice. The aim of this ethnographic study was to explore how the nursing assistants knowledge can be shared in a team on a spinal cord injury rehabilitation ward. Using a sociomaterial perspective on practice, we captured different aspects of interprofessional collaboration in health care. The findings reveal how knowledge was shared between professionals, depending on different kinds of practice architecture. These specific cultural-discursive, material-economic, and social-political arrangements enabled possibilities through which nursing assistants knowledge informed other practices, and others knowledge informed the practice of nursing assistants. By studying what health care professionals actually do and say in practice, we found that the nursing assistants could make a valuable contribution of knowledge to the team.

  • 131.
    Lindh Åstrand, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Hoffmann, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Spetz Holm, Anna-Clara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Use of hormone therapy (HT) among Swedish women with contraindications - A pharmacoepidemiological cohort study2019In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 123, p. 55-60Article in journal (Refereed)
    Abstract [en]

    Objectives: To assess how women in Sweden with breast cancer (BC), endometrial cancer (EC), and/or pulmonary embolism (PE) were dispensed menopausal hormone therapy (HT). Study design: A retrospective study of Swedish women aged 40 years or more on 31 December 2005 (n = 2,863,643), followed through to December 2011. The study analysed three mandatory national healthcare registries: the Swedish Prescribed Drug Register, the National Inpatient Register and the Cancer Register. New users were defined as having a first dispensation after at least a 9-month break, and thus were possible to identify from April 2006. New users with at least one of the diagnoses BC, EC or PE before the first dispensation were classified as having a relative or absolute contraindication for HT. Main outcome measures: The relative risks of having HT dispensed after being diagnosed with BC, EC and/or PE. Results: In total, 171,714 women had at least one of the diagnoses BC, EC or PE. The relative risk of having hormone therapy dispensed (current and new users) after being diagnosed with any of the diagnoses was significantly lower (PE, IRR 0.11, 95% CI 0.10-0.12;/ BC, IRR 0.12, 95% CI 0.11-0.13; EC, IRR 0.43, CI 0.40-0.46) than for women without these diagnoses. Conclusions: One in about 250 women started treatment with HT after being diagnosed with BC, PE or EC. Swedish prescribers seem to be well aware of the recommendations for HT use in women with contraindications. A few women, however, are prescribed HT despite having BC, EC or PE, possibly after careful evaluation of the risks and benefits and giving informed consent. Women with a history of PE were prescribed transdermal HT to a larger extent than women in general, in line with results from observational studies.

  • 132.
    Lindqvist, Emma
    et al.
    Highland Hospital, Sweden.
    Wedin, Madelene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Lymphedema after treatment for endometrial cancer - A review of prevalence and risk factors2017In: European Journal of Obstetrics, Gynecology, and Reproductive Biology, ISSN 0301-2115, E-ISSN 1872-7654, Vol. 211, p. 112-121Article, review/survey (Refereed)
    Abstract [en]

    Lymphedema is one of the least studied complications of cancer treatment and a chronic condition with a substantial impact on health-related quality of life (HQoL). Lymphedema of the legs (LLL) constitutes a common adverse side effect of lymphadenectomy LA in gynecologic cancer treatment. Primary treatment of endometrial cancer (EC) comprises hysterectomy and bilateral salpingo-oophorectomy. Pelvic and para-aortic lymphadenectomy is recommended in prognostic high risk groups of EC. This review summarizes the published literature concerning the prevalence of LLL after treatment for EC, methods used for measuring LLL, risk factors and HQoL impact. The main findings are that the reported prevalence of LLL varies significantly between 0% and 50%. This is due to a lack of a generally accepted standardization of terminology in assessment of lymphedema. The studies use different methods to assess and grade lymphedema and often the methodology used for determining LLL is poorly described and lacks baseline measurement. Lymphadenectomy, number of lymph nodes removed, and radiation therapy seems to increase the risk for LLL. All studies dealing with HQoL show that women with LLL have impaired HQoL. The level of evidence in the published studies is generally low. Consequently it is difficult to make clear-cut conclusions about the true prevalence or determination of risk factors. More prospective longitudinal or randomized trials with LLL as the primary outcome are necessary before conclusions can be drawn regarding prevalence of LLL and risk factor determination in EC. An internationally accepted standardization for terminology and methodology in lymphedema in research is needed. (C) 2017 Elsevier B.V. All rights reserved.

  • 133.
    Lindqvist, Maria
    et al.
    Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Sweden.
    Persson, Margareta
    Department of Nursing, Umeå University, Sweden.
    Nilsson, Margareta
    Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Sweden.
    Uustal, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Lindberg, Inger
    Luleå University of Technology, Department of Health Science, Division of Nursing, and Sunderby Research Unit, Umeå University, Sweden.
    ‘A worse nightmare than expected’: a Swedish qualitative study of women's experiences two months after obstetric anal sphincter muscle injury2018In: Midwifery, ISSN 0266-6138, E-ISSN 1532-3099, Vol. 61, p. 22-28Article in journal (Refereed)
    Abstract [en]

    Objective

    this study explores women's experiences of the first two months after obstetric anal sphincter injury (OASIS) during childbirth with a focus on problematic recovery.

    Methods

    this qualitative study used inductive qualitative content analysis to investigate open-ended responses from 1248 women. The data consists of short and comprehensive written responses to open-ended questions focusing on recovery in the national quality register, the Perineal Laceration Register, two months after OASIS at childbirth.

    Results

    the theme ‘A worse nightmare than expected’ illustrated women's experiences of their life situation. Pain was a constant reminder of the trauma, and the women had to face physical and psychological limitations as well as crushed expectations of family life. Furthermore, navigating healthcare services for help added further stress to an already stressful situation.

    Conclusions

    we found that women with problematic recovery two months after OASIS experienced their situation as a worse nightmare than expected. Extensive pain resulted in physical and psychological limitations, and crushed expectations of family life. Improved patient information for women with OASIS regarding pain, psychological and personal aspects, sexual function, and subsequent pregnancy delivery is needed. Also, there is a need for clear organizational structures and information to guide help-seeking women to needed care.

  • 134.
    Lingetun, Lovisa
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Fungbrant, Madicken
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Claesson, Ing-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Baggens, Christina
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    'I just want to be normal' - A qualitative study of pregnant women's blogs who present themselves as overweight or obese2017In: Midwifery, ISSN 0266-6138, E-ISSN 1532-3099, Vol. 49, p. 65-71Article in journal (Refereed)
    Abstract [en]

    Objective: to describe what pregnant women who present themselves as overweight or obese write about their pregnancy in their blogs.

    Setting: Swedish private blogs.

    Design: a qualitative study, using 13 Internet blogs as the source of data. Google was used to find the blogs. The blog content was analysed using thematic analysis.

    Findings: three main themes were identified: Pregnancy as an excuse, Perspectives on the pregnant body and Becoming a mother. The pregnancy was used as an excuse for breaking the norms, ‘I am normal because I am pregnant’, and gaining weight, ‘I normalise my weight and weight gain’. The women expressed different perspectives of their body through ‘ For me it is important to look pregnant’, ‘How others seem to see me’ and ‘Labelled a risk pregnancy at the antenatal care’. The transition to motherhood was described in ‘How the pregnancy affects my life’, and there was disappointment when the women experienced ‘Unmet expectations’.

    Key conclusion: the women described themselves as normal behind the obesity and saw their pregnancy as an excuse for their body size and behaviour. They did not identify themselves as a risk group and they did not recognise the midwife's support during the pregnancy.

    Implication for practice: midwives may have to address overweight and obese pregnant women's attitude towards weight and weight gain in weight gain interventions.

  • 135.
    Ljunggren, Carl Gustaf
    et al.
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Stenhammar, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Strömberg, Leif
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Icons in paediatrics: Rolf Kostmann (1909-1982)2017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 7, p. 1070-1072Article in journal (Other academic)
    Abstract [en]

    In the medical literature, diseases and syndromes are sometimes named after the first person to publish a report on, or describe, a condition. This is, of course, a great honour, both for the physician and his or her country and only a handful of Swedish medical researchers have achieved this. Swedish paediatrician Rolf Kostmann (Fig. 1) joined this elite group following his report on what he called infantile hereditary agranulocytosis (agranulocytosis infantilis hereditaria), which was first published 1950 in Swedish (1), and his dissertation in 1956 (2), He was the first to describe severe chronic neutropenia as an inherited disease. This article is protected by copyright.

  • 136.
    Long, Anna E.
    et al.
    Univ Bristol, England.
    Wilson, Isabel V.
    Univ Bristol, England.
    Becker, Dorothy J.
    Univ Pittsburgh, PA 15260 USA.
    Libman, Ingrid M.
    Univ Pittsburgh, PA 15260 USA.
    Arena, Vincent C.
    Univ Pittsburgh, PA 15260 USA.
    Wong, F. Susan
    Cardiff Univ, Wales.
    Steck, Andrea K.
    Univ Colorado, CO USA.
    Rewers, Marian J.
    Univ Colorado, CO USA.
    Yu, Liping
    Univ Colorado, CO USA.
    Achenbach, Peter
    Tech Univ Munich, Germany; Tech Univ Munich, Germany.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Williams, Alistair J. K.
    Univ Bristol, England.
    Gillespie, Kathleen M.
    Univ Bristol, England.
    Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 6, p. 1484-1490Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of slow progressors (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Methods Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Barts Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed amp;lt; 5 years old from BOX) using the chi(2) test. Results In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. Conclusion No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.

  • 137.
    Lucas, Steven
    et al.
    Uppsala University, Sweden.
    Bartas, Anna
    Växjö Regional Hospital, Sweden.
    Edstedt Bonamy, Anna-Karin
    Stockholm South Gen Hospital, Sweden.
    Tornudd, Lisa
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Wide, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Otterman, Gabriel
    Uppsala University, Sweden.
    Editorial Material: The way forward in addressing abusive head trauma in infants - current perspectives from Sweden in ACTA PAEDIATRICA, vol 106, issue 7, pp 1033-10352017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 7, p. 1033-1035Article in journal (Other academic)
    Abstract [en]

    n/a

  • 138.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Etiken måste få väga tyngre än juridiken vid sena aborter [Ethics must be more important than the law in late abortions].2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Other academic)
  • 139.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    GAD65: a prospective vaccine for treating Type 1 diabetes?2017In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 17, no 8, p. 1033-1043Article, review/survey (Refereed)
    Abstract [en]

    Introduction: In spite of modern techniques, the burden for patients with type 1 diabetes (T1D) will not disappear and T1D remains a life-threatening disease causing severe complications and increased mortality. We have to learn how to preserve residual insulin secretion or even increase beta cell regeneration. This would give a milder disease, simpler treatment and perhaps even cure. Thus, there are good reasons to try therapies that may preserve beta cell function.Areas covered: In this review the author reviews the literature and registered ongoing trials using GAD-alum put in relation to the high number of published different immune interventions.Expert opinion: GAD-alum treatment is safe, tolerable and easy for the patients and healthcare. It seems probable that treatment with GAD65-alum 20 mu g sc can preserve residual beta cell function in T1D, but efficacy needs to be improved. This may be achieved by the use of combination therapies and new approaches for administration.

  • 140.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Increasing Incidence but Decreasing Awareness of Type 1 Diabetes in Sweden2017In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 40, no 10, p. E143-E144Article in journal (Other academic)
    Abstract [en]

    n/a

  • 141.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Nej – barn med typ 1-diabetes lever inte i ständig livsfara2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115Article in journal (Other academic)
  • 142.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    No acute pancreatitis but reduced exocrine pancreatic function at diagnosis of type 1 diabetes in children2019In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448Article in journal (Refereed)
    Abstract [en]

    Background Insulitis in type 1 diabetes (T1D) seems to be both mild and rather rare, and immune cells are found also in the exocrine pancreas, which often is small. We wanted to see whether clinical pancreatitis at diagnosis of T1D in children is a commonly missed diagnosis. Methods Clinical symptoms suggesting pancreatitis were investigated in a retrospective case-control study in 191 newly diagnosed T1D patients (105 boys, 86 girls) with age at onset 0.2 to 18 (mean = 10.05, SD = 4.71, median = 10.36) years, 23/191 (12%) with ketoacidosis at diagnosis. Blood samples were taken on day 4 and stored at -20 degrees C until analyses for P-amylase and C-reactive protein (CRP), and compared with 100 age-matched healthy control children with plasma stored at -80 degrees C, and 46 with plasma stored at -20 degrees C. Results At diagnosis, 23/191 (12%) patients had mild transient abdominal pain, 2/23 with obstipation, and 5/23 also transient mild diarrhea. Five of 23 patients with abdominal pain had pH amp;lt; 7.30. None had clinical acute pancreatitis. One diabetic patient had P-amylase 1.3 mu kat/L (normal range = 0.15-1.1 mu kat/L), while 62/191 (32.4%) diabetic children had P-amylase below the normal range. None (0/100) of the -80-controls and only 1/46 (0.14 mu kat/L) of the -20-controls had the P-amylase level in the normal range. Five diabetic children, but no controls, had increased CRP, but not related to P-amylase or to gastrointestinal symptoms. Conclusions Acute pancreatitis seems to be very rare at diagnosis of T1D, but decreased exocrine function quite common, which supports that T1D sometimes is part of a more generalized pancreatic disorder.

  • 143.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Time to leave rigid traditions in Type 1 diabetes research2017In: Immunotherapy, ISSN 1750-743X, E-ISSN 1750-7448, Vol. 9, no 8, p. 619-621Article in journal (Other academic)
    Abstract [en]

    n/a

  • 144.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Vi måste bli bättre på att diagnostisera typ 1-diabetes [Diagnostics of type 1 diabetes must be improved]2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115Article in journal (Other academic)
    Abstract [sv]

    Incidence of type 1 diabetes in children and adolescents continues to increase but diagnosis is often delayed and keto-acidosis too common. More information is needed. General auto-antibody screening can be discussed.

  • 145.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Jones, Michael P.
    Macquarie University, Australia.
    Olsen Faresjö, Åshild
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Worm infestations and development of autoimmunity in children - The ABIS study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e173988Article in journal (Refereed)
    Abstract [en]

    Worm infestations influence the immune system and may therefore decrease the risk for autoimmune diseases. The aim of the study was to determine whether children who have developed autoimmune disease were less likely to have had worm infestations in childhood. The ABIS-study is a prospective population-based cohort study of children born in southeast Sweden 1997/99. 17.055 children participated. As of June 2014 116 individuals had developed Type 1 diabetes, 181 celiac disease, and 53 Juvenile Rheumatoid Arthritis. The parents answered questions on worm infestations when the children were 1, 5 and 8 years of age. The ABIS registry was connected to the National Registry of Drug Prescriptions, and national registries for diagnosis of the studied diseases. We found no differences in incidence of worm infestations at 1, 5 or 8 years of age between children who developed autoimmune disease(s) or healthy controls. At 8 years in total 20.0% of the general child population had experienced a worm infestation; children who developed Type 1 diabetes, 21,3%, celiac disease 19,5% and JRA 18,8%. There was no difference in prescriptions of drugs for treatment of worm infestations between those who had and who had not developed Type 1 diabetes, celiac disease, Juvenile Rheumatoid Arthritis. We found no associations indicating that worm infestations in childhood does not play a role in the development of autoimmune diseases in Sweden.

  • 146.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Lefebvre, Pierre
    Univ Liege, Belgium.
    Nerup, Jorn
    Gentofte Univ Copenhagen, Denmark.
    It is time to restore Rules for Authorship of scientific publications2018In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 19, no 3, p. 586-586Article in journal (Other academic)
    Abstract [en]

    n/a

  • 147.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Tavira Iglesias, Beatriz
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    More on Intralymphatic Injection of Autoantigen in Type 1 Diabetes REPLY2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 4, p. 403-405Article in journal (Other academic)
    Abstract [en]

    n/a

  • 148.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Letter: Intralymphatic Injection of Autoantigen in Type 1 Diabetes in NEW ENGLAND JOURNAL OF MEDICINE, vol 376, issue 7, pp 697-6992017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, no 7, p. 697-699Article in journal (Other academic)
    Abstract [en]

    n/a

  • 149.
    Lundgren, Cecilia
    et al.
    Department of Obstetrics and Gynecology, Kalmar County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Physiology , Kalmar County Hospital, Kalmar, Sweden.
    Wanby, Anna-Stina
    Department of Obstetrics and Gynecology , Kalmar County Hospital , Kalmar , Sweden.
    Cedergren, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Ante- and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy2018In: The Journal of Maternal-Fetal & Neonatal Medicine, ISSN 1476-7058, E-ISSN 1476-4954, Vol. 31, no 12, p. 1595-1601Article in journal (Refereed)
    Abstract [en]

    To identify obstetrical risk factors for the diagnosis of neonatal hypoxic ischemic encephalopathy (HIE). A secondary aim was to determine the incidence of HIE.

  • 150.
    Lundin, Cecilia
    et al.
    Uppsala University, Sweden.
    Gemzell Danielsson, Kristina
    Karolinska Institute, Sweden.
    Bixo, Marie
    Umeå University, Sweden.
    Moby, Lena
    Uppsala University, Sweden.
    Bengtsdotter, Hanna
    University of Örebro, Sweden.
    Jawad, Izabella
    University of Örebro, Sweden.
    Marions, Lena
    Karolinska Institute, Sweden.
    Brynhildsen, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Malmborg, Agota
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Lindh, Ingela
    Gothenburg University, Sweden.
    Sundstrom Poromaa, Inger
    Uppsala University, Sweden.
    Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle-A double-blind, placebo-controlled randomized trial2017In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 76, p. 135-143Article in journal (Refereed)
    Abstract [en]

    Objective: Ever since the introduction of combined oral contraception (COC), one of the major reasons for discontinuing the pill use has been mood-related side effects. Moreover, women who discontinue the pill turn to less effective methods whereby the probability of an unintended conception increases. Approximately 4-10% of COC users complain of depressed mood, irritability or increased anxiety, but drug-related causality has been difficult to prove. Given the lack of randomized controlled trials in this area, we aimed to prospectively estimate the severity of adverse mood in COC users that would be as representative of general users as possible. Methods: This investigator-initiated, multi-center, randomized, double-blinded, placebo-controlled study included 202 healthy women. Women were randomized to a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo for three treatment cycles. Main outcome measure was the Daily Record of Severity of Problems (DRSP), which was filled out daily during one baseline cycle and the final treatment cycle. Results: Results from 84 women in the COC group and 94 women in the placebo group were analysed. COC use was associated with small, but statistically significant, increases in mean anxiety (0.22; 95% CI: 0.07-0.37, p = 0.003), irritability (0.23; 95% CI: 0.07-0.38, p = 0.012), and mood swings scores (0.15; 95% CI: 0.00-0.31, p = 0.047) during the intermenstrual phase, but a significant premenstrual improvement in depression (-0.33; 95% CI: -0.62 to -0.05, p = 0.049). Secondary analyses showed that women with previous adverse hormonal contraceptive experience reported significantly greater mood worsening in the intermenstrual phase in comparison with healthy women, p amp;lt;0.05. The proportion of women who reported a clinically relevant mood deterioration did not differ between those allocated to COC (24.1%) or placebo (17.0%), p = 0.262. Conclusion: COC use is associated with small but statistically significant mood side effects in the inter menstrual phase. These findings are driven by a subgroup of women who clearly suffer from COC-related side effects. However, positive mood effects are noted in the premenstrual phase and the proportion of women with clinically relevant mood worsening did not differ between treatment groups. (C) 2016 Elsevier Ltd. All rights reserved.

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