Early treatment for cryptorchidism may be necessary to preserve fertility. International guidelines now recommend that congenital cryptorchidism be treated with orchiopexy before age 1 year. Acquired cryptorchidism should be treated at presentation. To our knowledge the rate of adherence to these guidelines in recent years is unknown. Thus, we present data on age at cryptorchidism diagnosis and orchiopexy in recent Danish birth cohorts.
A population of 508,964 Danish boys born alive from January 1, 1995 to December 31, 2009 was identified using the Danish Civil Registration System. Five birth cohorts were defined, including 1995 to 1997, 1998 to 2000, 2001 to 2003, 2004 to 2006 and 2007 to 2009. The boys were followed in the Danish National Patient Registry for a diagnosis of cryptorchidism and for an orchiopexy procedure. Data were analyzed using the Kaplan-Meier estimator and Cox regression models.
During followup 10,094 boys were diagnosed with cryptorchidism, of whom 5,473 underwent orchiopexy. Mean age at diagnosis in boys followed at least 6 years was 3.3 years (95% CI 3.3-3.4) in the 1995 to 1997 cohort, 3.1 (95% CI 3.1-3.2) in the 1998 to 2000 cohort and 2.9 (95% CI 2.8-2.9) in the 2001 to 2003 cohort while mean age at orchiopexy was 3.8 (3.7-3.9), 3.6 (3.5-3.7) and 3.3 years (3.2-3.4), respectively.
In the more recent birth cohorts of 1995 to 2009 we observed a shift toward younger age at cryptorchidism diagnosis and orchiopexy.
Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function.
We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression.
Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3.
Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.
Early delivery and low birth weight are strong predictors of the urogenital anomalies cryptorchidism (undescended testis) and hypospadias. Understanding these associations may lead to important etiologic clues. Therefore, the authors revisited the prevailing hypotheses regarding fetal growth restriction as a risk factor for urogenital anomalies. They studied a population of 934,538 Danish boys born alive between January 1, 1980, and December 31, 2008. Cryptorchidism and hypospadias were associated with low weight-for-gestational-age, an indicator of fetal growth restriction, and furthermore the authors observed strong interaction with early delivery. Low birth weight in a singleton compared with the mean birth weight of all singleton brothers in the family or in a twin compared with the male co-twin was associated with higher risk of urogenital anomalies, suggesting an effect of relative fetal growth restriction within families. Contrary to previous reports, newborns' body dimensions assessed independently of birth weight were not associated with urogenital anomalies. The hypothesis that shared factors cause both fetal growth restriction and urogenital anomalies was supported by comparison of urogenital anomaly risks in singletons and twins and by patterns of cryptorchidism and hypospadias co-occurrence in individuals. These novel insights might also extend to other male reproductive conditions with prenatal etiology.
OBJECTIVE: To study concordance rates of cryptorchidism (undescended testis) in pairs of boys with varying family structure, to evaluate the risk contribution from the intrauterine environment and genetic factors. DESIGN: Population based study of 1,024,500 Danish boys born from January 1, 1973 to December 31, 2004. Classic twin method and computerized square dance design. SETTING: Hospitals and outpatient clinics. PATIENT(S): Six groups of boy pairs: boys with no relation, paternal half-brothers, maternal half-brothers, full brothers, dizygotic twin brothers, and monozygotic twin brothers. INTERVENTION(S): Observational study. MAIN OUTCOME MEASURE(S): Status on each individual regarding cryptorchidism and orchiopexy from the Danish National Patient Register. RESULT(S): Concordance rates of cryptorchidism in the groups were as follows: boys with no relation 3.2% (95% confidence interval 2.7%-3.6%), paternal half-brothers 3.4% (2.3%-4.7%), maternal half-brothers 6.0% (4.5%-7.7%), full brothers 8.8% (8.3%-9.8%), dizygotic twin brothers 24.1% (16.0%-33.6%), and monozygotic twin brothers 27.3% (15.5%-41.2%). CONCLUSION(S): The concordance rate was higher in maternal than in paternal half-brothers, and much higher but of equal magnitude in both twin groups. The findings strongly support that the intrauterine environment and maternal inheritance are contributing to the occurrence of cryptorchidism.
Preterm and growth restricted infants may have developmental delays and deviations from normal organ function related to the gastrointestinal tract and the central nervous system. Since both organ systems are hypothesised to be involved in the pathogenesis of infantile colic, a condition characterised by excessive crying during the first months of life, impaired fetal growth and preterm birth may be risk factors for infantile colic.
A total of 62,761 liveborn singletons from the Danish National Birth Cohort (1996 to 2002) were studied. Infantile colic was defined according to Wessel's modified criteria based on maternal interview conducted at 6 months post-partum.
A total of 2605 (4.2%) infants were born preterm, 54,441 (86.7%) at term, and 5715 (9.1%) post-term. A total of 4964 (7.9%) infants fulfilled Wessel's modified criteria for infantile colic. The risk for infantile colic increased with decreasing gestational age after adjustment for covariates. The highest odds [odds ratio (95% confidence interval)] was observed for infants born before 32 completed gestational weeks (1.5 [95% CI 1.0, 2.2], reference: 40 gestational weeks). Small for gestational age infants (birthweight below 10th percentile) had an increased odds of infantile colic (1.2 [95% CI 1.1, 1.3]) in all gestational age groups.
We observed an increased risk of infantile colic in preterm and small for gestational age infants in a large cohort. Our results suggest that the aetiology of infantile colic may be found in the prenatal, perinatal, and neonatal period.
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.
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.
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.
We observed no association between maternal bereavement before and during pregnancy and the occurrence of cryptorchidism in the offspring.
Cyclooxygenase (COX) inhibitors-acetaminophen, ibuprofen and acetylsalicylic acid-have endocrine-disruptive properties in the rainbow trout. In humans, aspirin blocks the androgen response to human chorionic gonadotropin (hCG), and, because hCG-stimulated androgen production in utero is crucial for normal testicular descent, exposure to COX inhibitors at vulnerable times during gestation may impair testicular descent. We examined whether prenatal exposure to acetaminophen, ibuprofen, and acetylsalicylic acid was associated with increased occurrence of cryptorchidism.
Our study used data on 47,400 live-born singleton sons of mothers enrolled in the Danish National Birth Cohort during 1996-2002. Cryptorchidism was identified in 980 boys during childhood, of whom 565 underwent orchiopexy. The use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy was assessed in 3 computer-assisted telephone interviews and 1 self-administered questionnaire. We estimated adjusted hazard ratios (HRs) of cryptorchidism by Cox regression analysis.
Exposure to acetaminophen during both the first and second trimesters was associated with increased occurrence of cryptorchidism (HR = 1.33 [95% confidence interval = 1.00-1.77]). Exposure for more than 4 weeks within the postulated time-window of programming testicular descent (gestational weeks 8-14) was associated with a HR of 1.38 (1.05-1.83) for cryptorchidism. Exposure to ibuprofen and acetylsalicylic acid was not associated with cryptorchidism.
Maternal intake of acetaminophen for more than 4 weeks during pregnancy, especially during the first and second trimesters, may moderately increase the occurrence of cryptorchidism.
To investigate the associations between use of nicotine replacement therapy (NRT) and smoking during pregnancy and infantile colic in the offspring.
We used data from maternal interviews (from pregnancy and at 6 months post partum) from the Danish National Birth Cohort (1996-2002). We included 63?128 live-born singletons with complete information on nicotine exposure during pregnancy and infantile colic symptoms as recorded at 6 months of age.
A total of 46?660 infants (73.9%) were unexposed to nicotine during pregnancy; 207 (0.3%) were exposed to NRT, 15?016 (23.8%) were exposed to smoking, and 1245 (2.0%) to both. A total of 4974 (7.9%) infants fulfilled Wessel's modified criteria for infantile colic. Prenatal nicotine exposure was associated with elevated risk for infantile colic in the offspring. Compared with the unexposed, NRT users had an adjusted odds ratio (OR) (95% confidence interval) of 1.6 (1.0-2.5; P = .03), smokers had OR = 1.3 (1.2-1.4), and women who both smoked and used NRT had OR = 1.6 (1.3-1.9). Partners' smoking was not associated with infantile colic after adjustment for maternal smoking.
We corroborated the association between smoking and infantile colic after adjustment for several possible confounders in a large cohort study. Moreover, we found that infants exposed to NRT prenatally had an increased risk for infantile colic of the same magnitude as those exposed to tobacco smoke. Thus, nicotine may play a role in the pathogenesis of infantile colic.
Measures of prenatal environmental exposures are important, and amniotic fluid levels may directly reflect fetal exposures during hypothesized windows of vulnerability.
We aimed to detect various phthalate metabolites and perfluorooctanesulfonic acid (PFOS) in human amniotic fluid, to study temporal exposure trends, and to estimate potential associations with gestational week of amniocentesis and maternal age and parity at amniocentesis.
We studied 300 randomly selected second-trimester amniotic fluid samples from a Danish pregnancy-screening biobank covering 1980 through 1996. We used only samples from male offspring pregnancies. We assayed the environmental pollutants by liquid chromatography/triple quadrupole mass spectrometry and analyzed data using generalized linear regression models.
We detected the di(2-ethylhexyl) phthalate (DEHP) metabolite mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP) at a median concentration of 0.27 ng/mL [interquartile range (IQR): 0.20-0.37 ng/mL], the diisononyl phthalate (DiNP) metabolite mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP) at 0.07 ng/mL (IQR: 0.05-0.11 ng/mL), and PFOS at 1.1 ng/mL (IQR: 0.66-1.60 ng/mL). An increase of 1 calendar year was associated with 3.5% lower [95% confidence interval (CI): -4.8%, -2.1%] 5cx-MEPP levels and with 7.1% higher (95% CI: 5.3%, 9.0%) 7cx-MMeHP levels. For each later gestational week of amniocentesis, 5cx-MEPP was 9.9% higher (95% CI: 4.8%, 15.2%), 7cx-MMeHP was 8.6% higher (95: CI: 2.7%, 14.9%), and PFOS was 9.4% higher (95: CI: 3.3%, 15.9%). We observed no associations with maternal age or parity.
Measured metabolite levels appeared to parallel decreasing DEHP exposure and increasing DiNP exposure during the study period. The environmental pollutant levels were positively associated with later gestational age at amniocentesis during pregnancy weeks 12-22.
Previous studies indicate an increased risk of cryptorchidism, incomplete testicular descent, among sons of women working with pesticides. This study assessed the risk of cryptorchidism among boys of parents employed as horticultural workers and farmers using nationwide registers on occupation and cryptorchidism.
The cohort consisted of >600 000 boys born in Denmark from 1980-2007 with a parent in employment during pregnancy. These boys were followed for cryptorchidism from 1980-2009 comparing risks among sons of horticultural workers and farmers with sons of parents in other occupations. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox regression adjusting for parental age, birth years, parity, and geographical region.
Sons of maternal farmers were at increased risk of cryptorchidism (157 cases; HR 1.31, 95% CI 1.12-1.53) compared to boys of mothers in other occupations (15 511 cases). Paternal occupation as farmer was unrelated to the risk among sons. Maternal occupation as a horticultural worker was associated with a non-significantly increased risk (72 cases; HR 1.20, 95% CI 0.95-1.52). A similar association was found for paternal horticultural workers. Sons of maternal farmers or horticultural workers who likely worked in the first trimester were not at increased risk of cryptorchidism.
This nationwide cohort study found a slightly increased risk of cryptorchidism in sons of maternal horticultural workers and farmers. However, subgroup analyses indicated similar findings for paternal horticultural workers, and no association for women likely working in the first trimester. The main findings should therefore be interpreted with caution.