The ethical framework for performing research with rare inherited neurometabolic disease patients.

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families. CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied.

Perinatal conditions related to growth restriction and inflammation are associated with an increased risk of bronchopulmonary dysplasia.

AIM: Bronchopulmonary dysplasia (BPD) is a frequent chronic lung disease in preterm infants, and we aimed to identify factors associated with this condition in infants with respiratory distress syndrome (RDS). METHODS: This case-control study, using national Swedish data, included 2255 preterm infants, born before 33 gestational weeks. The 667 BPD cases were oxygen dependent at 36 weeks' postmenstrual age, and the 1558 controls only had RDS. Comparisons included perinatal conditions and pharmacological treatments. Adjusted odds ratios with 95% confidence intervals were calculated in a conditional logistic regression model, with gestational age as the conditioning term. RESULTS: An increased risk of BPD was associated with prelabour preterm rupture of membranes of more than 1 week (3.35, 2.16-5.19), small for gestational age (2.73, 2.11-3.55), low Apgar score (1.37, 1.05-1.81), patent ductus arteriosus (1.70, 1.33-2.18), persistent pulmonary hypertension (5.80, 3.21-10.50), pulmonary interstitial emphysema (2.78, 1.37-5.64), pneumothorax (2.95, 1.85-4.72), late onset infections (2.69, 1.82-3.98), intubation (1.56, 1.20-2.03), chest compressions (2.05, 1.15-3.66) and mechanical ventilation (2.16, 1.69-2.77), but not antenatal corticosteroids. CONCLUSION: Growth restriction and inflammation increased the risk of BPD in preterm infants and prelabour preterm rupture of membranes, small for gestational age, low Apgar score or need for resuscitation should raise clinical suspicions.

Prenatal inflammatory risk factors for development of bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious, chronic lung disease affecting preterm infants. OBJECTIVE: To identify prenatal risk factors for BPD, focusing on inflammation. METHODS: Observational cohort study including 106,339 preterm infants, live born before gestational week 37 + 0, from 1988 to 2009 in Sweden. A total of 2,115 infants were diagnosed with BPD, of which 1,393 were born extremely preterm, before gestational week 28 + 0. Information on risk factors was obtained from national health registers and included maternal chronic inflammatory diseases, pregnancy related diseases, and drugs related to treatment of inflammation or infection during pregnancy. Adjusted odds ratios (OR) were calculated in multivariable logistic regression models and are presented with 95% confidence intervals [95% CI]. RESULTS: Preeclampsia was the strongest risk factor for BPD [adjusted OR 2.04, 95% CI 1.83, 2.29]. For extremely preterm infants the adjusted OR was 1.33 [95% CI 1.08, 1.64]. Chorioamnionitis was associated with an increased risk of BPD, but only when including all infants in the analyses [OR 1.33, 95% CI 1.19, 1.48]. No apparent associations were found between maternal chronic inflammatory disease or use of anti-inflammatory drugs and the risk of BPD. Maternal diabetes mellitus, gestational diabetes and maternal use of antibiotics were associated with reduced risks of BPD. CONCLUSION: Preeclampsia related disorders increased the risk and maternal diabetes mellitus and gestational diabetes reduced the risk for BPD. As angiogenic factors play a role in preeclampsia and diabetes our findings suggest that an impaired angiogenesis may contribute to BPD development.

Antibiotic prescription preferences in paediatric outpatient setting in Estonia and Sweden.

Aims of the study were to compare the paediatric outpatient antibiotic use in two countries with low overall antibiotic consumption and antibacterial resistance levels - Sweden and Estonia - and to describe the adherence to Estonian treatment guideline. All prescriptions for systemic antibiotics for children less than 18 years during 2007 from the Swedish Prescribed Drug Register and Estonian Health Insurance Fund database were identified to conduct a descriptive drug utilisation study. The total paediatric antibiotic use was 616 and 353 per 1000 in Estonia and Sweden, respectively. The greatest between country differences occurred in the age group 2 to 6 years -Estonian children received 1184 and Swedish children 528 prescriptions per 1000. Extended spectrum penicillin amoxicillin (189 per 1000) or its combination with beta-lactamase inhibitor (81 per 1000) and a newer macrolide clarithromycin (127 per 1000) were prescribed most often in Estonia whereas narrow spectrum penicillin phenoxymethylpenicillin (169 per 1000) and older generation macrolide erythromycin (21 per 1000) predominated in Sweden. For acute bronchitis, 17 different antibiotics (most commonly clarithromycin) were prescribed in Estonia despite the guideline recommendation not to use antibiotics. The higher rate of antibiotic use especially of extended spectrum antibiotics in Estonia compared to Sweden emphasizes the need for national activities to promote appropriate use of antibiotics while treating children, even when the overall antibiotic consumption is low.

Health consequences of prophylactic exposure to antenatal corticosteroids among children born late preterm or term.

OBJECTIVE: To investigate the duration of effects and health consequences of earlier antenatal corticosteroid exposure in infants born late preterm or term. DESIGN: Observational cohort study. SETTING: Children born after gestational week 34 in Sweden, 1976-1997, whose mothers were hospitalized for imminent preterm delivery. The children were followed to their 11th birthday. SAMPLE: The cohort consisted of 11 873 infants, of whom 8620 were exposed. METHODS: Exposure was estimated at hospital level. Infants born at a hospital practicing antenatal corticosteroid administration were classified as exposed. Estimation of hospital routines was based on questionnaire data, telephone interviews with physicians and pharmacy sales, validated in a random sample of medical records. Logistic regression was used to assess associations with adjustments for pregnancy length, birth year and hospital level. MAIN OUTCOME MEASURES: Rates and odds ratios of mortality, respiratory distress syndrome, bronchopulmonary dysplasia, epilepsy, cerebral palsy, childhood diabetes, birthweight, length and head circumference for all infants, and for preterm and term infants, respectively. RESULTS: Exposed infants had reduced risks of respiratory distress syndrome (odds ratio 0.54, 95% confidence interval 0.35-0.83) and small head circumference (odds ratio 0.47, 95% confidence interval 0.36-0.61), and an increased risk of low Apgar scores (odds ratio 1.40, 95% confidence interval 1.01-1.94), most pronounced in infants born after gestational week 37. CONCLUSIONS: Infants born after gestational week 34 seem to benefit from earlier antenatal corticosteroid administration, with reduced risks of respiratory distress syndrome. However, the treatment was less beneficial for term infants, because they also had increased risk of low Apgar scores.

Reductions in use of hormone replacement therapy: effects on Swedish breast cancer incidence trends only seen after several years.

Studies from Western countries have found evidence of a recent decline in breast cancer incidence rates in postmenopausal women, findings which have been hypothesized to reflect a reduced use of hormonal replacement therapy (HRT). We examined breast cancer incidence trends in Sweden between 1997 and 2007, a period characterized by a drop in the use of HRT. Incidence trends were assessed using data from three population-based Regional Clinical Registries on breast cancer covering 2/3 of the Swedish population. Information on HRT sales was obtained from national pharmacy data. The prevalence of HRT use in age group 50-59 years decreased from a peak of 36% in 1999 to 27% in 2002 and further to 9% in 2007. Incidence rates of breast cancer in women 50 years and older increased between 1997 and 2003. A significant decrease in incidence between 2003 and 2007 was confined to women 50-59 years of age, the group in which the prevalence of HRT use has been highest and the decrease in use most pronounced. As opposed to the immediate effects reported from the United States and other regions, there was a time lag between the drop in HRT use and clear reductions in breast cancer incidence. This may reflect between country differences with regard to types of HRT used, and the rate, magnitude and pattern of change in use. The present findings give further support to the notion that HRT use is a driver of breast cancer incidence trends on the population level.

Short and long-term effects of antenatal corticosteroids assessed in a cohort of 7,827 children born preterm.

OBJECTIVE: To study the benefits of antenatal corticosteroids (ACS) in clinical settings and to evaluate the occurrence of long-term neuro-sensory effects such as epilepsy and cerebral palsy (CP). DESIGN: Observational population-based study including all births between gestational weeks 24 and 34 during 1976-1997 in Sweden. Exposure to ACS was evaluated at hospital level. Children were followed up to their ninth birthday. SAMPLE AND METHODS: Seven thousand eight hundred twenty-seven infants of which 5,632 were exposed to ACS. Data on hospital ACS routines was based on questionnaires and interviews with physicians and pharmacy sales. Outcomes were obtained from the national health registers and assessed according to gender of the child. Logistic regression was used to assess associations. MAIN OUTCOME MEASURES: Neonatal death, low Apgar score, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), CP, and epilepsy. RESULTS: After adjustment, exposed infants had reduced risks of RDS (OR 0.80, 95% CI 0.70-0.92), late neonatal death (OR 0.86, 95% CI 0.57-1.29), BPD (OR 0.87, 95% CI 0.62-1.22), ROP (OR 0.80, 95% CI 0.48-1.32), IVH (OR 0.93, 95% CI 0.67-1.3), and CP (OR 0.82, 95% CI 0.58-1.15). Males had a higher risk of epilepsy (OR 1.74, 95% CI 0.85-3.55) than females (OR 0.50, 95% CI 0.25-1.03). CONCLUSION: The results confirm the beneficial effect of ACS regarding RDS in clinical settings. Except for a tendency to increased risk of epilepsy among male infants there were no increased risks of neuro-sensory outcomes.

Limited knowledge on progestogen-only contraception and risk of venous thromboembolism.

OBJECTIVE: To assess the current knowledge concerning progestogen-only contraception (POC) and risks of venous thromboembolism (VTE). DESIGN AND SETTING: Systematic review of the literature on observational and analytical studies reporting risk estimates for VTE in women exposed to POCs. METHODS AND MAIN OUTCOME MEASURES: We performed a computerized literature search in the Pub Med, Embase, and the Cochrane Library for studies published between 1966 and February 13, 2008. Based on the evaluated studies we calculated an overall risk estimate for VTE in association with POC. RESULTS: Four case-control studies and one cohort study were included. Of the case-control studies, three reported an increased risk and one a decreased risk of VTE. The cohort study found divergent results depending on the type of statistical analysis used. None of the results was statistically significant. The overall odds ratio for POC-associated VTE in the four case-control studies was 1.45 (95% CI=0.92-2.26). CONCLUSIONS: The risk of VTE associated with use of POCs is poorly investigated. The slightly elevated overall risk estimate might suggest an association between POC and an increased risk for VTE. The results must, however, be interpreted with caution due to the possibility of residual confounding. Well-designed studies with sufficient statistical power to evaluate risks of VTE with POC are warranted.

Prevalence of psychiatric disorders and premenstrual dysphoric symptoms in patients with experience of adverse mood during treatment with combined oral contraceptives.

BACKGROUND: Negative mood symptoms remain one of the major reasons for discontinuation of combined oral contraceptive pills (COCs). The primary aim of this study was to compare the prevalence of mood and anxiety disorders in women with different experience of COCs. STUDY DESIGN: Thirty women currently on COCs with no report of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects, 33 women who had discontinued COC use due to adverse mood effects and 27 women who had discontinued COC use for reasons other than adverse mood symptoms were included. Ongoing psychiatric disorders were evaluated by a structured psychiatric interview and prevalence rates of premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) were assessed by daily prospective ratings on the Cyclicity Diagnoser scale. RESULTS: Women with ongoing or past experience of COC-induced adverse mood, more often suffered from mood disorders than women with no reports of adverse mood while on COC. The prevalence of prospectively defined PMS or PMDD did not differ between prior users with positive or negative experience. Women who had discontinued COC use due to adverse mood symptoms more often had had a legal abortion in the past. CONCLUSION: Women with ongoing or past self-reported adverse mood effects from COCs had a significantly increased prevalence of mood disorders.

Adverse mood effects of combined oral contraceptives in relation to personality traits.

OBJECTIVE: Mood symptoms, such as depressed mood, anxiety and increased irritability, remain one of the major reasons for discontinuation of combined oral contraceptive (COC) pills. The aim of this study was to compare personality traits in women with ongoing or previous use of COCs and different experiences from these compounds with respect to adverse mood symptoms. STUDY DESIGN: Thirty women currently on COCs with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 33 women who had discontinued COC use due to adverse mood effects were included. All participants were asked to fill out the Swedish universities Scales of Personality (SSP) to assess different personality traits. RESULTS: The women who were experiencing mood-related side effects on their current COC use exhibited higher scores on the somatic anxiety and stress susceptibility traits as compared to the women who did not experience any mood-related side effects from their current COCs. Women who had discontinued COC treatment because of adverse mood effects had higher scores of detachment and mistrust compared to women who had discontinued COC for reasons unrelated to mood effects. CONCLUSION: Higher scores on specific personality traits such as somatic anxiety and stress susceptibility are found in women with ongoing experience of adverse mood symptoms from COC. Higher scores of mistrust and detachment are more common among women who have discontinued COC treatment due to adverse mood effects.

Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls.

BACKGROUND: Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition (PPI) in women with different experience of oral contraceptive pills. METHODS: Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78, or 86dB. RESULTS: Patients with adverse mood effects of COCs exhibited lower levels of PPI with 86dB prepulse compared to COC users with no adverse effects of COCs (p<0.05). There was no difference in PPI between the two groups of prior COC users. No significant difference was found between the groups regarding acoustic startle response. CONCLUSION: Relative to COC users with no reports of adverse mood symptoms, subjects suffering from COC-induced negative mood displayed deficits in PPI of acoustic startle. The fact that there was no difference in PPI between the two groups of prior COC users indicates that deficient PPI is related to adverse mood effects caused by COCs.

Characteristics of women at low risk of STI presenting with pelvic inflammatory disease.

OBJECTIVE: To investigate the background and reproductive history of women who are considered at low risk of sexually transmitted infection (STI) presenting with acute pelvic inflammatory disease (PID). METHODS: Case-control study, investigating 51 women admitted to hospital with a diagnosis of acute PID and 50 healthy women attending for routine gynecological checkup. RESULTS: Women with PID were older (p = 0.003) and more often unemployed (p = 0.008), and had a lower educational level (p = 0.000003). Healthy women reported more regular routine attendance to gynecologists (p = 0.0008) and were less often smokers (p = 0.0009). There was no difference between groups regarding age at first sexual intercourse, number of sex partners during life, duration of current sexual partnership, and frequency of sexual intercourse, total number of deliveries, spontaneous abortions, ectopic pregnancies and outcome of last pregnancy. The number of induced abortions was significantly higher in the PID group (p = 0.0004). There were no differences between the groups with regard to previous episodes of PID. Healthy controls more often reported a history of STI (p = 0.00007). IUD was the most commonly reported current contraceptive method in both groups, and there was no difference in contraceptive practices between groups. CONCLUSION: Women with PID differed from healthy controls only with regard to socio-demographic characteristics and not with regard to common risk factors for PID.

Practices and perceptions on intrauterine contraception among Latvian obstetrician-gynecologists.

BACKGROUND: To investigate the professional activity and perceptions of intrauterine contraception among Latvian obstetrician-gynecologists. METHODS: A questionnaire was completed by 122 Latvian obstetrician-gynecologists attending an annual meeting. Statistical analysis was done with the Epi-Info 2002 statistical package. RESULTS: Every day contraceptive consulting was done by 91.8% of physicians and 98.4% reported ever having inserted intrauterine contraception. The majority of doctors reported careful selection of intrauterine contraception candidates, including screening for sexually transmitted infections before insertion. Intrauterine contraception insertion was definitely excluded in women without a stable monogamous relationship only by 9.8%. A causal relationship between intrauterine contraception and pelvic inflammatory disease was believed by 52.5%. Many doctors sometimes prescribed prophylactic antibiotics before or immediately after intrauterine contraception insertion. However, antibiotics were never prescribed before intrauterine contraception insertion by 50.8%. Younger doctors had significantly more often themselves used combined oral contraceptives than had older doctors, whereas older doctors more often had been intrauterine contraception users. Of current and former intrauterine contraception users, 93.4% were satisfied with this contraceptive method. CONCLUSIONS: Latvian obstetrician-gynecologists have wide experience in contraception counseling of intrauterine contraception, but some gaps in the theoretical knowledge of doctors about intrauterine contraception were identified. We could not find any significant differences in attitudes to and personal experience with contraceptive methods between older and younger generations, nor were there any differences between genders of obstetrician-gynecologists.

Abortion rate and contraceptive practices in immigrant and Swedish adolescents.

STUDY OBJECTIVE: To analyze if immigrant girls request early pregnancy termination more frequently than ethnic Swedish girls and, if so, study possible explanations, including contraceptive practices and attitudes. DESIGN AND PARTICIPANTS: All women under 19 years of age who attended a large abortion clinic during one year were interviewed. Out of 126 adolescents, 36% were born outside Sweden. The immigrant girls (37 born abroad and 23 with at least one parent born abroad) were compared to 66 ethnic Swedish girls regarding contraceptive habits, reasons for abortion and social factors. RESULTS: The proportion of adolescents born abroad was larger than expected: 38 (29%) were born outside Sweden, compared to 18% in corresponding areas of Stockholm. The ethnic Swedish girls had fewer previous pregnancies than first and second generation immigrants and had more experience of contraceptive counselling. The most common reason for abortion in both groups was the wish to finish education. Ethnical Swedish girls claimed young age as reason for abortion more often than immigrants; economic reasons and reasons related to partner relationship were also common. CONCLUSION: First generation immigrant girls are over-represented among adolescents who seek termination of pregnancy. This can be explained by the fact that the immigrant girls had less experience of contraceptive use and contraceptive counselling than ethnical Swedish girls.

"Older" age is a risk factor for pelvic inflammatory disease in intrauterine device users.

BACKGROUND: To asses the role of a copper intrauterine device (IUD) per se in the development of pelvic inflammatory disease (PID) and complicated PID in women considered at low risk of PID. METHODS: Cases were 51 women admitted to hospital with a diagnosis of acute PID, and controls were 50 healthy women attending an outpatient clinic for routine gynecological check-up. The women were 25-45 years old. Data were analyzed and compared between groups using the statistical program package sas. RESULTS: IUD use was not associated with an increased risk of PID in general, but in women > or =35 years, IUD use was associated with a risk of PID [odds ratio (OR) = 4.2, confidence interval (CI) 1.1-16.3]. When adjusting for smoking, educational level, employment, and microbial findings in women with PID, IUD use was associated with complicated PID in women > or =35 years (OR = 33.9, CI 1.2-959.6), but not in younger women. When adjusting age and IUD use duration for each other in IUD users, age > or =35 years was a significant risk factor for PID (OR = 4.9, CI 1.3-19.2), but not long (> or =5 years) duration. In IUD users with PID, age > or =35 years was a risk factor for a PID to be complicated in both the unadjusted and adjusted analysis (OR = 12.7, CI 1.6-102.3; OR = 12.1, CI 1.4-104.7), whereas long duration of IUD use was not. When adjusting for significant endocervical microbial findings, long duration of IUD use and age, only age > or =35 years, remained significantly associated with both PID and complicated PID (OR = 5, CI 1.1-21.9; OR = 36, CI - 1.9-670). CONCLUSIONS: IUD use was not associated with PID in low-risk younger women, but in women > or =35 years, IUD use was associated with an increased risk of PID. The study also demonstrates an association between IUD use and complicated PID in women > or =35 years.