Chromosome errors in human eggs shape natural fertility over reproductive life span.

Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.

Fertility preservation and refreezing of transplanted ovarian tissue-a potential new way of managing patients with low risk of malignant cell recurrence.

OBJECTIVE: To report the first successful refreezing of ovarian tissue recovered more than 3 years after transplantation in a woman previously treated for early-stage ovarian cancer. DESIGN: Evaluation of cryopreserved and grafted ovarian tissue. SETTING: University hospital. PATIENT(S): A 23-year-old woman diagnosed with stage 1C ovarian mucinous cystadenocarcinoma. INTERVENTION(S): The patient underwent ovarian tissue cryopreservation for fertility preservation and subsequent heterotopic transplantation for fertility restoration 9 years after freezing. After a successful IVF twin pregnancy, grafted tissue was laparoscopically removed for safety reasons. The recovered tissue was refrozen. MAIN OUTCOME MEASURE(S): Live birth and histologic evaluation of the distribution of pre-antral follicle stages. RESULT(S): The previously grafted ovarian tissue was successfully refrozen, presenting follicular survival 4 weeks after xenografting. The follicular distribution in the recovered grafts showed a shift toward growing-stage follicles compared with the fresh tissue. The patient subsequently entered menopause, and histologic evaluation revealed a total of five follicles in two remaining grafts which had supported ovarian function a few months earlier. CONCLUSION(S): This is the second case of delivery following heterotopic grafting as well as the second case of successful transplantation of ovarian tissue from a patient with early-stage ovarian cancer. The recovered grafts showed that a lower number of functional follicles than previously estimated can actually support ovarian function. Removing and refreezing grafted tissue could be a new way of handling not only cancer patients with a risk of malignant cell recurrence, but also certain groups of patients with genetic conditions.

Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study.

STUDY QUESTION: What is the prevalence of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome? SUMMARY ANSWER: The prevalence of MRKH syndrome in Denmark is 1 in 4982 (95% confidence interval (CI): 4216-5887) live female births. WHAT IS KNOWN ALREADY: The prevalence of MRKH syndrome has been estimated to be around 1 in 4000-5000 females. However, population-based prevalence studies of MRKH syndrome are sparse. Moreover, population-based data on patient characteristics are lacking. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study used the Danish National Patient Registry (DNPR) to identify a nationwide population-based cohort of patients with MRKH syndrome. Subsequently, patients were linked to the Danish Cytogenetic Central Registry (DCCR) and patient medical records in order to validate the diagnoses. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospitalizations and outpatient visits from 1994 to April 2015 at all public hospitals in Denmark were searched for patients assigned with a diagnosis code indicative of MRKH syndrome. The diagnoses were validated by diagnostic history in the DNPR and DCCR data, and by review of patient medical records. The prevalence was estimated considering the identified patients born from 1974 to 1996. Patient characteristics were described using data collected from DNPR, DCCR and patient medical records. MAIN RESULTS AND THE ROLE OF CHANCE: The diagnosis was validated in 304 of 314 patients (96.8%) suspected with MRKH syndrome by review of diagnostic histories, DCCR data, and medical records and in 168 patients, the diagnosis of MRKH syndrome was confirmed (positive predictive value = 55.3% (95% CI: 49.5-60.9%)). The prevalence was 1 in 4982 (95% CI: 4216-5887) live female births based on 138 patients born from 1974 to 1996. Typical MRKH syndrome and atypical MRKH syndrome/Müllerian duct aplasia, Renal aplasia, and Cervicothoracic Somite dysplasia association were present in 56.5% and 43.5% of the patients, respectively. Kidney malformations were the most prevalent extragenital malformations, described in 38 of 111 patients (34.2%). However, in 57 patients (33.9%) no urinary tract imaging was performed. Three familial cases of MRKH syndrome were identified. LIMITATIONS, REASONS FOR CAUTION: We identified all patients with MRKH syndrome diagnosed at public hospitals in Denmark. When interpreting the prevalence estimate, caution must be taken due to limitations such as patients not diagnosed in public hospitals, other diagnosis codes not used in the study and the unknown impact of a net positive migration rate in Denmark. WIDER IMPLICATIONS OF THE FINDINGS: The prevalence estimate around 1 in 5000 is in accordance with a previous nationwide study. We consider the prevalence generalizable to other Caucasian populations. Prevalence studies of non-Caucasian populations are needed to investigate whether inter-ethnic differences in prevalence exist. Finally, the results of this study emphasize the need for sufficient basic examinations of patients with MRKH syndrome, including the importance of family medical history. STUDY FUNDING/COMPETING INTERESTS: None.

Use of inhaled and oral corticosteroids in pregnancy and the risk of malformations or miscarriage.

Corticosteroids are potent anti-inflammatory and immunosuppressive drugs, which sometimes must be given to pregnant women. Corticosteroids have been suspected to be teratogenic for many years; however, there is conflicting evidence regarding the association. Based on a literature review of three databases, this MiniReview provides an overview of inhaled and oral corticosteroid use in pregnancy with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. The use of corticosteroids among pregnant women ranged from 0.2% to 10% and increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring; at the same time, published estimates are inconsistent. The use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage, whereas the use of oral corticosteroids was not; however, confounding by indication could not be ruled out.

Use of prescribed drugs among primiparous women: an 11-year population-based study in Denmark.

PURPOSE: To describe patterns of prescribed drug use over time among primiparous women in Denmark. METHODS: Through the Danish Medical Birth Registry, we identified all primiparous women giving live birth or stillbirth at ≥ 22 gestational weeks in northern Denmark, from 1999 to 2009. From the Aarhus University Prescription Database we obtained information on the women's prescriptions for reimbursed drugs filled from 30 days before conception until delivery. RESULTS: Among 85,710 primiparous women, 47,982 (56.0%) redeemed at least one prescription from 30 days before conception until delivery. Women aged 35 years and older had the highest overall prevalence of prescription drug use (61.1%). Age-standardized prevalence of drug use was 54.7% in 1999 and 61.2% in 2009, prevalence ratio (PR) of 1.13 (95% confidence interval 1.10; 1.16), adjusted for age and smoking. CONCLUSION: Over the 11-year period from 1999 to 2009, we found a modest increase in overall use of drugs by primiparous women in Denmark. This increase was not, however, explained by an increasing proportion of older first-time mothers. We noted changes in patterns of use of anti-infective drugs and antidepressants.

Hypothyroidism secondary to hypothalamic-pituitary dysfunction may be part of the phenotype in klinefelter syndrome: a case-control study.

CONTEXT: Klinefelter syndrome (KS) may involve a number of abnormalities besides the characteristic testicular insufficiency. Some studies have suggested that thyroid abnormalities may be common, but this has not been clarified. DESIGN: A case-control study of men with KS (n = 75) compared with age-matched men from the general population (n = 75) was organized, and thyroid function, thyroid volume by ultrasonography, and thyroid antibodies were examined. RESULTS: Men with KS were on average taller and heavier and tended to have a higher body mass index than the men in the control group. Serum free T(4) (fT4) was lower in men with KS than controls [mean (sd): 16.3 (2.35) vs. 17.6 (1.75) pmol/liter; P < 0.001], with clustering in or just below the lower part of the reference range for the assay. The ratio fT4 to free T(3) was low in KS (P < 0.001), whereas no differences between groups were observed in TSH, free T(3), TSH to fT4 ratio, thyroid volume, or the prevalence of thyroid antibodies. No difference in any of the variables were observed between testosterone-treated and untreated KS men. Adjustment for differences in height, weight, and concomitant disease in multivariate models did not alter the results. CONCLUSIONS: Men with KS had a general shift toward lower values in distribution of serum fT4 with no compensatory increase in serum TSH. The most likely mechanism is a decrease or change in set point of thyrotroph control of thyroid function.

Hospitalizations for opioid poisoning: a nation-wide population-based study in Denmark, 1998-2004.

AIMS: To assess hospitalization rates (HR) for poisoning with heroin, methadone or strong analgesics and relate them to quantities of prescribed methadone and strong analgesics in Denmark between 1998 and 2004. DESIGN: Population-based ecological study. SETTINGS: We extracted data on all emergency department visits and hospital admissions registered in the Danish National Patient Registry with a diagnosis of poisoning with heroin (n = 1688), methadone (n = 173) or strong analgesics (n = 384). To ascertain sale of prescribed medications we used data from the Danish Medicines Agency. MEASUREMENTS: Age- and gender-standardized HR and defined daily doses (DDD) per 1000 people per day. FINDINGS: HR for heroin poisoning was 4.4 [95% confidence interval (CI): 3.8-4.9] per 100,000 person-years (p-y) in 1998 and 4.6 (CI: 4.0-5.2) per 100,000 p-y in 2004. HR for methadone poisoning increased from 0.1 (CI: 0.0-0.2) per 100,000 p-y in 1998 to 1.1 (CI: 0.8-1.4) per 100,000 p-y in 2004. HR for poisoning with strong analgesics increased from 0.6 (CI: 0.4-0.9) per 100,000 p-y in 1998 to 2.1 (CI: 1.8-2.6) per 100,000 p-y in 2004. The sale of prescribed strong analgesics (5.0 DDD per 1000 people per day in 1998 to 5.9 DDD in 2004) and methadone (3.0 DDD per 1000 people per day in 1998 to 3.4 DDD in 2004) increased slightly between 1998 and 2004. CONCLUSION: Increasing sale of prescribed methadone and strong analgesics coincided with increasing HRs of poisoning with these drugs, whereas HR of heroin poisoning varied. Further longitudinal studies are important for the guidance of future policy making.

[Extrapulmonary complications of Mycoplasma pneumoniae infections]. / Ekstrapulmonale komplikationer ved mycoplasma pneumoniae-infektioner.

INTRODUCTION: Mycoplasma pneumoniae is a common cause of atypical pneumonia in children and young adults. The infection is generally mild and only a very few patients are admitted to hospital. However, extrapulmonary complications are well recognised--mostly as manifestations from the central nervous system (CNS). MATERIAL AND METHODS: We describe 21 patients with M. pneumoniae infection seen at Rigshospitalet, Copenhagen, from 1994 to 2000. RESULTS: The patients had fever, headache, myalgia, and cough. Biochemically, they were characterised by leucocytosis, an increased level of C-reactive protein, and infiltrations on the chest x-ray. A total of seven patients developed extrapulmonary complications to the infection in the form of encephalitis (3), polyradiculitis (1), transversel myelitis (1), erythema multiforme (3), cardial arrhythmia (1), and haemolytic anaemia (2). Three patients had more than one complication at the same time. DISCUSSION: The incidence of patients with complications to M. pneumoniae infection was higher than that reported in the literature, probably because these patients are typically submitted to the Department of Infectious Diseases, Rigshospitalet. The pathogenesis of extrapulmonary complications to M. pneumoniae infection is unknown.