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BACKGROUND: Although congenital abnormalities in the male reproductive tract are common, their causes remain poorly understood. We studied associations between hypertensive disorders of pregnancy (pre-gestational hypertension, gestational hypertension, and preeclampsia) and the genital anomalies, cryptorchidism (undescended testes), and hypospadias (ventrally displaced urethral meatus).METHODS: We established a population of 1,073,026 Danish boys born alive between 1 January 1978 and 31 December 2012. By means of Cox regression analyses, we estimated hazard ratios with 95% confidence intervals for cryptorchidism and hypospadias according to type and severity of hypertensive disorder. Further, we used restricted cubic spline analyses to investigate the association between gestational age at onset of severe and moderate preeclampsia and the two genital anomalies.RESULTS: We found associations between pre-gestational hypertension and cryptorchidism [HR: 1.3 (95% CI: 1.1, 1.6)] and hypospadias [HR: 1.7 (95% CI: 1.3, 2.3)], whereas gestational hypertension was only associated with cryptorchidism [HR: 1.2 (95% CI: 1.1, 1.4)]. Boys of mothers with preeclampsia had the highest occurrence of cryptorchidism and hypospadias, increasing with preeclampsia severity. Women with HELLP syndrome faced the highest risk of having a child with both cryptorchidism [HR: 2.1 (95% CI: 1.4, 3.2)] and hypospadias [HR: 3.9 (95% CI: 2.5, 6.1)]. Further, the occurrence increased with early onset of preeclampsia diagnosis.CONCLUSIONS: These findings support the hypotheses that preeclampsia and genital anomalies share common etiologic factors and that placental dysfunction and androgen deficiency in early pregnancy are important in the etiology of male genital anomalies.

BACKGROUND: Styrene is an important industrial chemical that the general population is exposed to at low levels. Previous research has suggested increased occurrence of leukemia and lymphoma among reinforced plastics workers exposed at high levels of styrene.METHODS: We followed 73,036 workers of 456 small- and medium-sized Danish reinforced plastics companies from 1968 to 2011 and investigated the exposure-response relation between cumulative styrene exposure and incidence of lymphohematopoietic malignancies. We modeled styrene exposure from employment history, survey data, and historical styrene exposure measurements. We retrieved information on lymphohematopoietic malignancies from national cancer and patient registers.RESULTS: We identified 665 cases overall of 21 different lymphohematopoietic malignancies or combinations thereof, each with at least 20 cases, during 1,581,976 person-years of follow-up. Initial analyses suggested higher age, sex, and calendar year-adjusted incidence rate ratios (RRs) for acute myeloid leukemia, Hodgkin lymphoma, and T-cell lymphoma with higher estimates of cumulative styrene exposure. Accounting for time since exposure showed a trend by cumulative styrene exposure (P = 0.01) and a doubled risk (RR = 2.4; 95% CI, 1.2, 4.6) of acute myeloid leukemia following estimated high compared with estimated low cumulative exposure during the prior 15-29 years. We observed no increased risk following exposure during more recent years and less consistent risk patterns for Hodgkin lymphoma and T-cell lymphoma.CONCLUSIONS: This study, to our knowledge the largest epidemiologic study to date of occupational styrene exposure, suggests increased risk of acute myeloid leukemia following high styrene exposure with a latency period of about 15 years.

BACKGROUND: Fertility treatment includes hormonal stimulation of the woman and in vitro manipulation of gametes and embryos that may influence prenatal brain development. We aimed to investigate the association between fertility treatment and childhood epilepsy, including specific types of treatment and indications as well as subtypes of epilepsy.METHODS: In this nationwide birth cohort study, we included all pregnancies in Denmark resulting in live-born singletons, 1995-2003. Children conceived by fertility treatment and children developing epilepsy (until 2013) were identified from Danish national registers.RESULTS: A total of 565,116 pregnancies were included; 8,071 children (1.4%) developed epilepsy.Children conceived after ovulation induction or intrauterine insemination had a slightly higher risk of childhood epilepsy (hazard ratio (HR) 1.15; 95% confidence interval (CI): 1.00 - 1.31). The association was more pronounced for the subtypes idiopathic generalized and focal epilepsy. Regarding the specific hormonal treatments, only clomiphene citrate was associated with an increased risk of childhood epilepsy, also in a sibling analysis (HR 2.07; 95% CI: 1.05 - 4.08).In vitro fertilization or intracytoplasmic sperm injection was not associated with an overall increased risk of childhood epilepsy but with idiopathic generalized epilepsy (HR 1.43; 95% CI: 0.99 - 2.05). No clear associations were seen regarding other treatment types or indications.CONCLUSIONS: Children conceived by ovulation induction or intrauterine insemination with clomiphene citrate may be at slightly increased risk of childhood epilepsy. Furthermore, children conceived by in vitro fertilization or intracytoplasmic sperm injection may be at slightly increased risk of idiopathic generalized epilepsy.

BACKGROUND: Occupational exposure to styrene is widespread and has been suggested to be carcinogenic. The aim of this study was to investigate whether occupational exposure to styrene increases the risk of cancer, in particular lymphohematopoietic cancers.METHODS: We established a study population of 72,292 workers employed in 443 small and medium-sized companies producing reinforced plastics 1964-2007 by utilizing several national registries, expert assessment, and worker survey data. We identified incident cancer cases from 1968 to 2012 in the national Danish cancer registry and computed standardized incidence rate ratios (SIRs) with 95% confidence intervals (95% CI) based on national rates.RESULTS: Increasing SIRs of Hodgkin lymphoma, myeloid leukemia, and cancer of nasal cavities and sinuses were inconsistently associated with increasing duration of employment, early year of first employment, or styrene exposure probability. No such trends were observed for cancer of the esophagus, pancreas, lung, kidney, or urinary bladder, which have previously been associated with styrene exposure. Lung cancer showed an overall increased risk that decreased by duration of employment CONCLUSION:: Occupational styrene exposure may be associated with Hodgkin lymphoma, myeloid leukemia, and cancer of nasal cavities and sinuses. Further studies are needed to evaluate if the observed associations are likely to be causal.