Persistence and risk factors of high-risk human papillomavirus infection among HIV positive and HIV negative tanzanian women: a cohort study.

BACKGROUND: High-risk (HR) human papillomavirus (HPV) persistence is the most important risk factor for cervical cancer. We have assessed the type-specific HR HPV persistence among HIV positive and HIV negative Tanzanian women and factors associated with HR HPV persistence. METHODS: In a cohort study including 4080 Tanzanian women, 3074 attended follow-up examination (up to 32 months after enrollment). Cervical samples were obtained for liquid-based cytology and HPV DNA testing using Hybrid Capture 2 and Inno-Lipa Extra II. Information on lifestyle factors was collected through a personal interview. The probability of HR HPV persistence at a given time point since enrollment was estimated non-parametrically using the EMICM algorithm. RESULTS: Among the 462 women HR HPV positive at enrollment, 158 had at least one identical type detected at follow-up. The probability of persistence at 18 months after enrollment was 34.2 (95% CI 29.0-39.4). Stratifying by HIV status, the persistence probability was 42.9% (95% CI 33.5-51.9) among HIV positive, and 28.0% (95% CI 22.1-34.2) among HIV negative. Overall, HR HPV persistence was most common for HPV58, 35, 16, 31, and 52. Among HIV positive women it was HPV45, and HPV16, followed by HPV58 and HPV18, and among HIV negative women it was HPV31, HPV33 and HPV58. Risk factors associated with persistence of HR HPV were older age, longer interval between enrollment and follow-up, binge drinking, and HIV status. CONCLUSIONS: HR HPV persistence was common in Tanzania, and most common among HIV positive women. Overall, persistence was most frequent for HPV 58, 35, 16, 31 and 52. The nonavalent HPV vaccine should be considered.

The association between human papillomavirus and cervical high-grade cytology among HIV-positive and HIV-negative Tanzanian women: A cross-sectional study.

INTRODUCTION: Human papillomavirus (HPV) is the causative agent of precancerous lesions and cervical cancer, cervical cancer being the leading cause of deaths in Tanzanian women. Early detection and treatment of precancerous lesions are important in the prevention of cervical cancer cases. MATERIAL AND METHODS: We conducted a cross-sectional study among 3390 Tanzanian women aged 25-60 years. Information on lifestyle habits was collected, and women underwent gynecological examination with collection of cervical cells for conventional cytological and HPV testing. Blood samples were tested for HIV. The association between cervical high-grade cytology (HGC) and potential risk factors was examined using multivariable logistic regression adjusting for age and high-risk HPV (HR-HPV). RESULTS: The prevalence of HGC was 3.6% and of low-grade cytology was 8.3%. In women who were both HR-HPV-positive and HIV-positive, the prevalence of HGC was 28.3%. It increased by age and was 47% among women aged 50-60 years. Women, who had their sexual debut at age 9-15 years and 16-18 years, respectively, had 2.5 and 2.4 times increased odds of HGC compared with women whose sexual debut was at age 21 years and older. HIV-positive women had increased odds of HGC in comparison with HIV-negative women after adjustment for age (odds ratio [OR] 2.95, 95% CI 1.92-4.54). HR-HPV-positive women had nearly 100-fold increased odds of HGC compared with HR-HPV-negative women (OR 96.6, 95% CI 48.0-194), and this estimate was higher among HIV-positive women (OR 152.2, 95% CI 36.1-642.0). CONCLUSIONS: Increasing age, early age at first intercourse, HR-HPV, and HIV infections were associated with a substantially increased risk of HGC.

Antidepressant use during pregnancy and risk of congenital heart defects: A case-time-control study.

PURPOSE: We estimated the association between maternal antidepressant (AD) use in early pregnancy and risk of congenital heart defects. METHODS: We applied a case-time-control design with the aim of controlling for confounding from time-invariant factors and compared the results of the design to results from a cohort design in a population of 792 685 singletons born alive in Denmark during 1995-2008. In the case-time-control design, we identified children diagnosed with a congenital heart defect in the first 5 years of life (cases) and compared maternal AD use in the risk period (the first 3 months of pregnancy) and the reference period (gestational months 5-7). A nondiseased control group was included to adjust for time trends of exposure. In the cohort design, we identified children whose mothers redeemed at least one AD prescription in the first 3 months of pregnancy (the exposed) and two other groups including the unexposed children with maternal AD prescriptions in the 12 months before pregnancy. We applied conditional logistic regression and logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The case-time-control OR for any congenital heart defect was 1.03 (95% CI, 0.61-1.73), which was similar to the OR (1.09, 95% CI, 0.88-1.35) from the cohort design when we compared the exposed children with the unexposed children with maternal AD use before pregnancy. CONCLUSIONS: The case-time-control design provided results similar to the cohort design when the cohort design had a better confounder control strategy. We discussed the strengths and drawbacks of case-time-control design.

Performance of careHPV, hybrid capture 2 and visual inspection with acetic acid for detection of high-grade cervical lesion in Tanzania: A cross-sectional study.

OBJECTIVE: To examine the test performance of careHPV, Hybrid Capture2 (HC2) and visual inspection with acetic acid (VIA) for detection of cytologically diagnosed high-grade cervical lesions or cancer (HSIL+). DESIGN: Cross-sectional study. SETTING: Ocean Road Cancer Institute (ORCI) and Kilimanjaro Christian Medical Center (KCMC), Tanzania. POPULATION: Women attending routine cervical cancer screening. METHOD: We enrolled 4080 women (25-60 years) in the study. The women were interviewed on lifestyle habits, and tested for HIV. A cervical specimen for careHPV testing (performed at ORCI and KCMC), and a liquid-based cytology sample for HPV DNA detection using HC2 (performed at Tuebingen University Hospital, Germany) and for cytology assessment (performed at Vejle Hospital, Denmark) were obtained at a gynecological examination. Subsequently, VIA was performed. With cytology as gold standard, the sensitivity and specificity of careHPV, HC2, and VIA for detection of HSIL+ were calculated. RESULTS: Altogether, 23.6% had a positive careHPV test, 19.1% had positive HC2 test, and 6.3% had a positive VIA test. The sensitivity/specificity was 88.9%/78.9% for careHPV and 91.1%/83.7%, for HC2. VIA showed a low sensitivity of 31.1% but a high specificity (94.6%) for detection of HSIL+. The sensitivity of careHPV, HC2 and VIA was higher among younger women, and among HIV positive women. VIA triage of careHPV positive women improved specificity, but sensitivity dropped to 27%. CONCLUSION: Our results confirm the low sensitivity of VIA for detection of HSIL+ and further document that careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions. A suitable triage test has to be identified.

Effect of pulsed electric field on structural properties and digestibility of starches with different crystalline type in solid state.

Effect of pulsed electric field (PEF) on the structural properties of representative starches with different crystalline type, wheat starch for type A, potato starch for type B, and pea starch for type C, were investigated with polarized light microscopy (PLM), X-ray diffractometry (XRD), attenuated total internal reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, small-angle X-ray scattering (SAXS), and gel permeation chromatography (GPC) to understand whether PEF could be applied directly in starchy foods. The results showed that PEF could change the structure of all three types of starch, especially potato starch; the birefringence, represented by Maltese cross in polarized microscopic observation changed slightly; XRD and SSNMR spectra demonstrated PEF did not change the crystalline type of starch granules. However, relative crystallinity variations happened at some points of electric field intensity (EFI). Increasing with the EFI, a bigger variation of R1045/1022 happened in potato starch than in wheat starch and pea starch, as illustrated by ATR-FTIR. Significant influences of PEF on the scatter structure and fractal dimension of self-similar structures were observed for wheat starch and potato starch, but not for pea starch. The GPC suggested that molecular weight distribution changed for all the three starches. And in vitro tests showed that PEF changed significantly (P < 0.05) the digestibility of starches, especially wheat starch and potato starch.

Intimate partner violence (IPV): The validity of an IPV screening instrument utilized among pregnant women in Tanzania and Vietnam.

BACKGROUND: Intimate partner violence (IPV) is a global problem that affects one-third of all women. The present study aims to develop and determine the validity of a screening instrument for the detection of IPV in pregnant women in Tanzania and Vietnam and to determine the minimum number of questions needed to identify IPV. METHOD: An IPV screening instrument based on eight questions was tested on 1,116 Tanzanian and 1,309 Vietnamese women who attended antenatal care before 24 gestational weeks. The women were re-interviewed during their 30th-34th gestational week where the World Health Organization (WHO) IPV questionnaire was used as the gold standard. In all, 255 combinations of eight different questions were first tested on the Tanzanian study population where sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. In the evaluation of the performance of the question combinations, different IPV types and the frequency of abusive acts were considered. The question combinations that performed best in Tanzania were subsequently evaluated in the Vietnamese study population. RESULTS: In Tanzania, a combination of three selected questions including one question on emotional IPV, one on physical IPV and one on sexual IPV was found to be most effective in identifying women who are exposed to at least one type of IPV during pregnancy (sensitivity = .80; specificity = .74). The performance of the identified combination was slightly less effective in Vietnam (sensitivity = .74; specificity = .68). Focusing on different IPV types, the best performance was found for exposure to physical IPV in both Tanzania (sensitivity = .93; specificity = .70) and Vietnam (sensitivity = .96; specificity = .55). In both countries, the sensitivity increased with the frequency of abuse whereas the specificity decreased. CONCLUSION: By asking pregnant women three simple questions we were able to identify women who were exposed to IPV during pregnancy in two different countries. The question combination performed best in assessing physical IPV where it identified 93% and 96% of Vietnamese and Tanzanian women, respectively, who were exposed to physical IPV.

Parental Rheumatoid Arthritis and Autism Spectrum Disorders in Offspring: A Danish Nationwide Cohort Study.

OBJECTIVE: Maternal rheumatoid arthritis (RA) has been associated with an increased risk of autism spectrum disorder (ASD) in the offspring. We assessed the potential influence of both maternal and paternal RA on the risk of ASD in offspring to disentangle the influence of genetic inheritance from other conditions potentially leading to fetal programming. METHOD: The nationwide cohort study included all children born alive from 1977 to 2008 in Denmark (N = 1,917,723). Cox regression models were used to calculate hazard rate ratios (HR) of ASD in offspring exposed to maternal or paternal RA, compared to unexposed children. RESULTS: Maternal RA was associated with an approximately 30% increased risk of ASD in the offspring (HR = 1.31 and 95% CI = 1.06-1.63). Also, paternal RA seemed to increase the risk of ASD by approximately 30% (HR = 1.33, 95% CI = 0.97-1.82). CONCLUSION: Our findings suggest maternal as well as paternal RA to be associated with an increased risk of ASD in the offspring, indicating that genetic factors associated with RA may also play a role in the etiology of ASD in children of parents with RA.

Parental rheumatoid arthritis and childhood epilepsy: A nationwide cohort study.

OBJECTIVE: To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy. METHODS: We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days-4 years), late childhood (5-15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010). RESULTS: Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13-1.60] and 1.26 [95% CI 1.13-1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92-1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81-1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26-2.86] vs HR 1.26 [95% CI 1.03-1.52], respectively [p = 0.16]). CONCLUSIONS: Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates that changes in the intrauterine environment may play a role.

Maternal Antenatal Bereavement and Neural Tube Defect in Live-Born Offspring: A Cohort Study.

BACKGROUND: Maternal emotional stress during pregnancy has previously been associated with congenital neural malformations, but most studies are based on data collected retrospectively. The objective of our study was to investigate associations between antenatal maternal bereavement due to death of a close relative and neural tube defects (NTDs) in the offspring. METHODS: We performed a register-based cohort study including all live-born children (N = 1,734,190) from 1978-2008. Exposure was bereavement due to loss of a close relative from one year before conception to the end of the first trimester of pregnancy. The outcome was NTDs in the offspring according to the International Classification of Disease. We used multivariate logistic regression to estimate prevalence odds ratios (ORs). RESULTS: A total of 2% children were born to mothers who lost a close relative prenatally. During 30 years of follow-up, 1,115 children were diagnosed with any NTDs: spina bifida (n = 889), anencephaly (n = 85) and encephalocele (n = 164). And 23 children were diagnosed with two types of NTDs. Overall, when comparing bereaved mothers to non-bereaved mothers, no significant increased prevalence of NTDs in the offspring was seen (OR = 0.84; 95% confidence interval: 0.52-1.33). CONCLUSION: Overall maternal bereavement in the antenatal period was not related to NTDs in liveborn offspring.

Cancer risk in siblings of children with congenital malformations.

PURPOSE: Cancer and birth defects cluster in families more often than expected by chance, but the reasons are neither well known nor well studied. METHODS: From singletons born alive in Denmark between 1 January 1977 and 31 December 2007, we identified children who had no congenital malformations but had a full or half sibling with a congenital malformation (CM) diagnosed in the first year of life; this constituted the exposed group, while children whose siblings had no such condition constituted a reference group. We estimated cancer risks for children who had a full sibling or a half sibling with a CM using a Cox proportional hazards regression model. To control for confounding related to change of family structure, we estimated cancer risks for children from core families and children from broken families separately. Children were followed from birth up to 30 years of age (median follow-up 13.6 years). We obtained information on CMs and cancer from the Danish National Hospital Register and the Danish Cancer Registry. RESULTS: We identified 991,454 (78%) children from core families with 53,995 children who had a full sibling with a CM and 277,773 (22%) children from broken families with 7200 children who had a full sibling with a CM and 6194 children who had a half sibling with a CM. Children who had a full sibling with a CM from both core and broken families showed, in general, no increased cancer risk compared with children whose siblings had no CM, except in the case of children who had a full sibling with a CM in the nervous system (HR=2.61, 95%CI:1.60-4.27) or in the eye, ear, face, or neck (HR=2.47, 95%CI: 1.46-4.18). Children who had a half sibling with a CM seemed to have a higher cancer risk in early adulthood (HR=1.87, 95%CI: 0.98-3.56). CONCLUSIONS: Children who had a full sibling with a CM had no increased risk of cancer except for those who had a full sibling with a CM in the nervous system or in the eye, ear, face or neck. Children with a half-sibling with a CM tended to have an increased cancer risk in early adulthood, perhaps a result of chance. This study should be replicated using other data sources.

Correction: Cancer Mortality in People Treated with Antidepressants before Cancer Diagnosis: a Population Based Cohort Study.

[This corrects the article DOI: 10.1371/journal.pone.0138134.].

Parental rheumatoid arthritis and long-term child morbidity: a nationwide cohort study.

OBJECTIVE: To estimate the influence of parental rheumatoid arthritis (RA) on child morbidity. DESIGN: Nationwide cohort study. SETTING: Individual linkage to nationwide Danish registries. PARTICIPANTS: All singletons born in Denmark during 1977-2008 (n=1 917 723) were followed for an average of 16 years. MAIN OUTCOME MEASURES: Adjusted HRs for child morbidity; that is, 11 main diagnostic groups and specific autoimmune diseases within the International Classification of Diseases 8th and 10th versions. RESULTS: Compared with unexposed children, children exposed to maternal RA ('clinical' and 'preclinical') (n=13 566) had up to 26% higher morbidity in 8 of 11 main diagnostic groups. Similar tendencies were found in children exposed to paternal RA ('clinical' and 'preclinical') (n=6330), with statistically significantly higher morbidity in 6 of 11 diagnostic groups. HRs were highest for autoimmune diseases with up to three times increased risk of juvenile idiopathic arthritis (HR, 95% CI 3.30, 2.71 to 4.03 and 2.97, 2.20 to 4.01) and increased risk of up to 40% of diabetes mellitus type 1 (HR, 95% CI 1.37, 1.12 to 1.66 and 1.44, 1.09 to 1.90) and up to 30% increased HR of asthma (HR, 95% CI 1.28, 1.20 to 1.36 and 1.15, 1.04 to 1.26). Conclusions were roughly similar for children exposed to maternal clinical RA and for children only followed up to 16 years of age. CONCLUSION: Children of parents with RA had consistent excess morbidity. If the associations reflect biological mechanisms, genetic factors seem to play an important role. These findings call for attention given to children of parents with RA.

Preparation of a Carbon Doped Tissue-Mimicking Material with High Dielectric Properties for Microwave Imaging Application.

In this paper, the oil-in-gelatin based tissue-mimicking materials (TMMs) doped with carbon based materials including carbon nanotube, graphene ink or lignin were prepared. The volume percent for gelatin based mixtures and oil based mixtures were both around 50%, and the doping amounts were 2 wt %, 4 wt %, and 6 wt %. The effect of doping material and amount on the microwave dielectric properties including dielectric constant and conductivity were investigated over an ultra-wide frequency range from 2 GHz to 20 GHz. The coaxial open-ended reflection technology was used to evaluate the microwave dielectric properties. Six measured values in different locations of each sample were averaged and the standard deviations of all the measured dielectric properties, including dielectric constant and conductivity, were less than one, indicating a good uniformity of the prepared samples. Without doping, the dielectric constant was equal to 23 ± 2 approximately. Results showed with doping of carbon based materials that the dielectric constant and conductivity both increased about 5% to 20%, and the increment was dependent on the doping amount. By proper selection of doping amount of the carbon based materials, the prepared material could map the required dielectric properties of special tissues. The proposed materials were suitable for the phantom used in the microwave medical imaging system.

Trends in All-Cause Mortality across Gestational Age in Days for Children Born at Term.

BACKGROUND: Term birth is a gestational age from 259 days to 293 days. However trends in mortality according to gestational ages in days have not yet been described in this time period. METHODS AND FINDINGS: Based on nation-wide registries, we conducted a population-based cohort study among all children born at term in Denmark from 1997 to 2004 to estimate differences in mortality across gestational ages in days among singletons born at term. We studied early-neonatal mortality, neonatal mortality, infant mortality, and five-year mortality. Children were followed from birth up to the last day of the defined mortality period or December 31, 2009. A total of 360,375 singletons born between 259 and 293 days of gestation were included in the study. Mortality decreased with increasing gestational age in days and the highest mortality was observed among children born at 37 week of gestation. A similar pattern was observed when analyses were restricted to children born to by mothers without pregnancy complications. CONCLUSIONS: This study demonstrates heterogeneity in mortality rates even among singletons born at term. The highest mortality was observed among children born 37 weeks of gestation, which call for cautions when inducing labor in term pregnancies just reaching 37 weeks of gestation. The findings support that 37 weeks of gestation should be defined as early term.

Cancer Mortality in People Treated with Antidepressants before Cancer Diagnosis: A Population Based Cohort Study.

BACKGROUND: Depression is common after a cancer diagnosis and is associated with an increased mortality, but it is unclear whether depression occurring before the cancer diagnosis affects cancer mortality. We aimed to study cancer mortality of people treated with antidepressants before cancer diagnosis. METHODS AND FINDINGS: We conducted a population based cohort study of all adults diagnosed with cancer between January 2003 and December 2010 in Denmark (N = 201,662). We obtained information on cancer from the Danish Cancer Registry, on the day of death from the Danish Civil Registry, and on redeemed antidepressants from the Danish National Prescription Registry. Current users of antidepressants were defined as those who redeemed the latest prescription of antidepressant 0-4 months before cancer diagnosis (irrespective of earlier prescriptions), and former users as those who redeemed the latest prescription five or more months before cancer diagnosis. We estimated an all-cause one-year mortality rate ratio (MRR) and a conditional five-year MRR for patients who survived the first year after cancer diagnosis and confidence interval (CI) using a Cox proportional hazards regression model. Overall, 33,111 (16.4%) patients redeemed at least one antidepressant prescription in the three years before cancer diagnosis of whom 21,851 (10.8%) were current users at the time of cancer diagnosis. Current antidepressant users had a 32% higher one-year mortality (MRR = 1.32, 95% CI: 1.29-1.35) and a 22% higher conditional five-year mortality (MRR = 1.22, 95% CI: 1.17-1.26) if patients survived the first year after the cancer diagnosis than patients not redeeming antidepressants. The one-year mortality was particularly high for patients who initiated antidepressant treatment within four months before cancer diagnosis (MRR = 1.54, 95% CI: 1.47-1.61). Former users had no increased cancer mortality. CONCLUSIONS: Initiation of antidepressive treatment prior to cancer diagnosis is common and is associated with an increased mortality.

Maternal preeclampsia and childhood asthma in the offspring.

BACKGROUND: Preeclampsia is a possible risk factor for childhood asthma in the offspring. Our aim was to find whether preeclampsia is associated with childhood asthma. We also aimed to study whether a possible association can be explained by factors shared by siblings. METHODS: All eligible live singletons born in Denmark during 1993-2007 were identified (N = 923,533), and the occurrence of preeclampsia during the index pregnancy was determined. The children were followed from their 3rd birthday to the first hospitalization, outpatient contact or prescription for asthma, emigration, death, their 18th birthday, or the end of 2010, whichever came first. We carried out a nested case-control and a case-sibling study with density sampling to estimate incidence rate ratio (IRR) of asthma as a function of maternal preeclampsia, using conditional logistic regression. RESULTS: A total of 115,522 asthma cases were identified during 1996-2010. In the case-control analysis, the overall IRR of asthma for those exposed to maternal preeclampsia was 1.19 (95% confidence interval (CI): 1.15, 1.24). The IRRs for asthma according to early and late onset preeclampsia were 1.88 (95% CI: 1.67, 2.11) and 1.14 (95% CI: 1.10, 1.19). In the case-sibling analysis, the corresponding IRRs were 1.06 (95% CI: 0.98, 1.14), 1.15 (95% CI: 1.02, 1.29), and 1.02 (95% CI: 0.93, 1.11), respectively. CONCLUSIONS: Early onset preeclampsia was associated with an increased risk of asthma in the offspring, but part of this association may be due to confounding by factors shared by siblings.

Medical augmentation of labor and the risk of ADHD in offspring: a population-based study.

BACKGROUND AND OBJECTIVE: Oxytocin for labor augmentation is widely used in obstetric care in Western countries. Two recent, smaller studies found opposing results regarding the association between prenatal exposure to oxytocin for labor augmentation and attention-deficit/hyperactivity disorder (ADHD). In Denmark, oxytocin is the medication used for nearly all medical augmentations of labor, and we examined the association between medical augmentation of labor and ADHD in a large cohort study based on national register data. METHODS: All singletons born after spontaneous onset of labor in Denmark between 2000 and 2008 (N = 546 146) were included in the study. Data from the Danish Medical Birth Registry on medical augmentation of labor (yes/no) were used to identify exposed children. ADHD was defined based on the diagnostic codes of International Classification of Diseases, 10th Revision, for hyperkinetic disorder and information on dispensed ADHD medication. A multivariate proportional hazards regression model was used to test the association. RESULTS: Among 546 146 deliveries, 26% included medical augmentation of labor, and 0.9% of the children were identified as having ADHD (n = 4617). We found no association between augmentation of labor and ADHD in the offspring (hazard ratio: 1.05 [95% confidence interval: 0.98-1.13]). CONCLUSIONS: Our study does not support an association between medical augmentation of labor and ADHD in the child.

Maternal bereavement and cryptorchidism in offspring.

BACKGROUND: Cryptorchidism (undescended testis) is a common anomaly with largely unexplained etiology. Animal studies have suggested maternal emotional stress as a potential risk factor, but this has not been studied in humans. We aimed to investigate whether maternal bereavement due to the death of a close relative in the antenatal period increases the occurrence of cryptorchidism in the offspring. METHODS: In a population-based cohort, we studied death of a close relative as the exposure and cryptorchidism entries in nationwide medical registries as the outcome. Danish national registries included 898,961 (23,609 exposed) boys born from 1978 to 2008 with a maximum of 30 years of follow-up. RESULTS: A total of 20,947 boys had cryptorchidism, of whom 13,524 also underwent corrective surgery. We found no increased occurrence of cryptorchidism in the offspring (hazard ratio = 1.02 [95% confidence interval = 0.92-1.14]). Results were similar when the diagnosis was verified with surgery. We adjusted for maternal and paternal age, birth year, and family history of cryptorchidism. CONCLUSION: We observed no association between maternal bereavement before and during pregnancy and the occurrence of cryptorchidism in the offspring.

Spontaneous abortion, stillbirth and hyperthyroidism: a danish population-based study.

OBJECTIVES: Pregnancy loss in women suffering from hyperthyroidism has been described in case reports, but the risk of pregnancy loss caused by maternal hyperthyroidism in a population is unknown. We aimed to evaluate the association between maternal hyperthyroidism and pregnancy loss in a population-based cohort study. STUDY DESIGN: All pregnancies in Denmark from 1997 to 2008 leading to hospital visits (n = 1,062,862) were identified in nationwide registers together with information on maternal hyperthyroidism for up to 2 years after the pregnancy [hospital diagnosis/prescription of antithyroid drug (ATD)]. The Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence interval (CI) for spontaneous abortion (gestational age <22 weeks) and stillbirth (≥22 weeks), reference: no maternal thyroid dysfunction. RESULTS: When maternal hyperthyroidism was diagnosed before/during the pregnancy (n = 5,229), spontaneous abortion occurred more often both in women treated before the pregnancy alone [aHR 1.28 (95% CI 1.18-1.40)] and in women treated with ATD in early pregnancy [1.18 (1.07-1.31)]. When maternal hyperthyroidism was diagnosed and treated for the first time in the 2-year period after the pregnancy (n = 2,361), there was a high risk that the pregnancy under study had terminated with a stillbirth [2.12 (1.30-3.47)]. CONCLUSIONS: Both early (spontaneous abortion) and late (stillbirth) pregnancy loss were more common in women suffering from hyperthyroidism. Inadequately treated hyperthyroidism in early pregnancy may have been involved in spontaneous abortion, and undetected high maternal thyroid hormone levels present in late pregnancy may have attributed to an increased risk of stillbirth.

Trimethoprim use before pregnancy and risk of congenital malformation: reanalyzed using a case-crossover design and a case-time-control design.

PURPOSE: Studies on the safety of drugs used during pregnancy are necessary and important but prone to bias. Using cases as their own controls can reduce bias. We used a case-crossover design and a case-time-control design to estimate the risk of congenital malformation (CM) for children born to mothers who redeemed a trimethoprim prescription shortly before pregnancy. METHODS: The study was based on all live born singletons (N = 685 600) in Denmark whose mothers had available information on prescriptions in the Danish National Prescription Registry between 1996 and 2008. We defined 1-3 months before pregnancy as a potential risk period and 13-15 months before pregnancy as a reference period. Two other reference periods were used (7-9 months before pregnancy and months 4-6 of pregnancy). The case-crossover design is dependent on the assumption of a stable trimethoprim prescription over the study period in the source population. To estimate the trend of trimethoprim prescriptions, we used a control group comprising children without CMs. RESULTS: Both study designs showed children had a higher risk of overall CM [odds ratio of 1.66, 95% confidence interval (CI): 1.10-2.53 and 1.50, 95%CI: 0.66-3.38, respectively] if their mothers had a trimethoprim prescription in the 3 months before pregnancy and subtypes of CM for example in the musculoskeletal system, which were consistent to the previous findings from a cohort study. CONCLUSIONS: This study corroborates that trimethoprim is a potential teratogen when used 3 months before pregnancy and demonstrates the value of case-only approaches for studying, for example, adverse effects of antibiotics in reproductive epidemiology.