Cryptorchidism (undescended testis) is one of the most common abnormalities in newborn boys worldwide, with etiology in nonsyndromic cases largely unknown.1 A prevalence of 2%-3% has been reported among newborn boys in Denmark.2 Maternal lifestyle factors and environmental exposures during pregnancy are suspected to interfere with normal testicular descent and to possibly increase the risk of cryptorchidism.1,3
Rat experimental models indicate the existence of a time window in which normal androgen action is crucial to the programming of future testicular descent.4 For humans, it is hypothesized that androgen activity around weeks 8-14 of gestation programs later transinguinal descent during weeks 26-35, which would move the susceptible time window to a much earlier gestational age than previously assumed.4 In humans, late transinguinal testicular descent is androgen-dependent and is most likely the part of the descent process that is most commonly affected in cryptorchid boys.5 Androgen production in the developing male gonad is driven by human chorionic gonadotropin (hCG) and luteinizing hormone (LH).6–8 Prostaglandins from the cyclooxygenase (COX) pathway have been associated with testosterone production in male rats,9 and in animal Leydig cells hCG-induced testosterone production is modulated by prostaglandins.10,11 The mechanisms in humans, however, are not yet fully elucidated.12 The COX inhibitors—acetaminophen, ibuprofen, and acetylsalicylic acid—have shown endocrine-disruptive properties in the rainbow trout, affecting steroid hormone synthesis.13 Studies in men have shown that, aspirin (acetylsalicylic acid) inhibits the androgen response to hCG.14 Since hCG-stimulated androgen production in utero is crucial to normal testicular descent,7 exposure to any COX inhibitor at vulnerable times during gestation may interfere with normal masculinization of the fetus. Acetaminophen, ibuprofen, and acetylsalicylic are widely used during pregnancy, and are known to cross the placental barrier.15,16 NSAIDs inhibit prostaglandin synthesis through inhibition of COX enzymes, with variable potency for COX-1 and COX-2.17 Acetaminophen exerts its COX-2 inhibitory effect primarily through a mechanism different from that of NSAIDs.18–20
To our knowledge, there are no published studies on the risk of cryptorchidism in humans following prenatal exposure to COX inhibitors. One recent analysis of acetaminophen and congenital malformations was conducted from the same cohort as used in the present study.21 That study was not designed to examine cryptorchidism specifically, but rather major congenital abnormalities, according to the European Surveillance of Congenital Abnormalities Classification (EUROCAT).22 Cryptorchidism is considered a minor malformation, and was registered only if it co-occurred with a major malformation. This excluded most nonsyndromic cryptorchidism cases. In the previous study, the hazard ratio (HR) of cryptorchidism in the presence of first-trimester acetaminophen exposure was 1.24 (0.79-1.94). We examined whether prenatal exposure to acetaminophen, ibuprofen, and acetylsalicylic acid—including exposures during the suggested male programming window (gestational weeks 8-14)—is associated with an increased occurrence of cryptorchidism.
METHODS
Study Population
The study is based on data from the Danish National Birth Cohort, a population-based cohort of children born to women who were pregnant during 1996-2002 and who intended to carry their pregnancy to term.23 At their first antenatal visit, pregnant women were invited by their general practitioner to join the cohort. Approximately 50% of all general practitioners in Denmark participated and nearly 60% of invited women consented to a series of telephone interviews on exposures during pregnancy and their child's health status. The interviews occurred around gestational weeks 17 and 32, and at 6 and 18 months after birth. Participants also completed a self-administered questionnaire at enrollment (between recognition of pregnancy and first telephone interview). Information provided on this questionnaire was checked and elaborated during the first telephone interview. Participants were asked to have prescriptions or medication packets available at the time of each interview. All Regional Science Ethics Committees in Denmark have approved the Danish national Birth Cohort; before we initiated this study, we obtained approval from the Danish Data Protection Agency.
Exposure Assessment
We defined exposure to acetaminophen, ibuprofen, or acetylsalicylic acid as self-reported use of drugs containing any of these active substances at least once during pregnancy. Data on exposure were collected both prospectively (before cryptorchidism could be recognized), by using the enrollment questionnaire and the 2 telephone interviews during pregnancy, and retrospectively (after cryptorchidism could be recognized) during the telephone interview that took place 6 months postpartum. The retrospective data concerned only the period between the second telephone interview (around gestational week 32) and delivery. Study questionnaires elicited the name of the drug and the timing of use on a weekly basis, and, taken together, covered from 4 weeks before pregnancy until delivery. Women were asked, “Have you taken any kind of pain killers?” If they answered “yes,” they were asked to specify which drug they used from a list of 44 specific painkillers, including acetaminophen, ibuprofen, and acetylsalicylic acid alone or in combination (both over-the-counter and prescribed drugs). Respondents were also given the option to provide the names of painkillers or other drugs not included in the list. For each drug reported, they were asked to specify in which gestational weeks they were used. Complementary questions were “Have you taken any medicine during pregnancy that we have not yet talked about?” A positive response then elicited the name and gestational weeks of exposure. Additional questions addressed antirheumatic drugs used for muscle or joint diseases and drugs used to treat fever, inflammation, or infections. The enrollment questionnaire asked women about any drug use from 4 weeks before the last menstrual period until 14 weeks afterward, including drug name and timing of use. Drugs containing acetaminophen, ibuprofen, or acetylsalicylic acid were classified according to the gestational week of reported use. Exposure status in a particular gestational week was rarely reported in more than 1 interview; when this occurred, exposure was considered present if reported in either of the 2 interviews. Discrepancies of exposure status between interviews for a given gestational week did not affect the trimester-specific definition of exposure. Gestational age was calculated from the first day of the last menstrual period and from routine obstetric ultrasonography examinations. The gestational age determined by ultrasonography was used in case of discrepancy between the 2 measures. We focused on ibuprofen and acetylsalicylic acid among the NSAIDs because they are the most commonly used in this population and because they are also available over-the-counter in Denmark.
Covariates
We decided a priori to adjust for the following potential confounders: maternal age in years at time of childbirth (<25, 25-29, 30-34, and ≥35 years)24; household occupational status (higher- or middle-grade professionals, skilled workers and students, and unskilled workers and unemployed); parity before birth of the index boy (0 and 1+)25,26; time to pregnancy (0-5, 6-12, 13+ months); treatment of infertility (yes vs. no)24,27; and maternal smoking during pregnancy (none, 1-10 and 11+ cigarettes per day).27Table 1 includes the approximate percentages of missing responses for each covariate.
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TABLE 1: Characteristics of 47,400 Mothers and Boys in the Danish National Birth Cohort, by Their Use of Acetaminophen, Ibuprofen, and Acetylsalicylic Acid During Pregnancy, 1996–2002
Outcome Measures
Information on cryptorchidism, other congenital malformations, and surgical procedures undergone by boys in the cohort was obtained from the Danish National Patient Registry. This registry contains information on all inpatient and outpatient clinic diagnoses and surgeries performed during the follow-up period.28 The registry covered 100% of Denmark's hospitals during the study period. The study used 2 endpoints with increasing diagnostic specificity: first, boys with a diagnosis of cryptorchidism coded in accordance with the International Classification of Diseases 10 (ICD10 codes: Q53, Q531, Q531A, Q532, Q532A, and Q539); second, boys with a diagnosis of cryptorchidism who also underwent orchiopexy (codes KKFH00, KKFH01, and KKFH10 in the Nordic Classification of Surgical Procedures). Orchiopexy indicates that the cryptorchidism is persistent, while the diagnosis of cryptorchidism also covers transient cases of undescended testes that descend spontaneously.
Statistical Methods
Although cryptorchidism is considered a congenital malformation, not all cases are identified at birth. Some, including recurrences, are diagnosed and treated throughout childhood.29 The boys in the Danish National Birth Cohort had not reached an age where all cryptorchidism cases had been identified,30 nor had they all attained the same age by the end of follow-up: the youngest boy was 6 years old and the oldest 13 years old. To account for variation in follow-up periods, we estimated crude and adjusted HRs by means of Cox regression models, using boy's age as the time variable. The boys entered the risk set at birth and were followed until their age at first diagnosis, death, emigration from Denmark, or end of follow-up (21 October 2009), whichever came first. The proportional hazards assumption was checked by visual inspection of log-minus-log plots.
We analyzed separate and combined exposures to acetaminophen, ibuprofen, and acetylsalicylic acid. For acetaminophen, we were able to study exposure by trimester. For ibuprofen and acetylsalicylic acid, the number of exposed boys was small, allowing only dichotomous analysis of exposure. For acetaminophen exposure during the entire pregnancy, we compared no exposure (no acetaminophen exposure at any time during pregnancy) with exposure only during 1 trimester (each separately), exposure only during both the first and second trimesters, exposure only during both the second and third trimesters, and exposure during all 3 trimesters. By applying this grouping, each woman was counted only once in this model. Exposure during weeks 8-14 (the suggested male-programming window) was analyzed in a separate model, including observations already counted in the analysis of acetaminophen exposure during entire pregnancy.
In a “dose-response” analysis, we compared mothers with increasing number of exposed weeks during gestation (1, 2-4, 5-8, 9-12, and >12 weeks) to unexposed mothers. Although the comparison is crude—for example, 8 tablets a day for 5 weeks was grouped together with 2 tablets a day for 5 weeks—it gives some information on accumulated weeks of exposure. A “dose-response” analysis was also done for weeks 8-14 with a cut point of 4 weeks chosen prior to analysis. In both analyses on weeks of exposure, we excluded 7294 women who (due to changes in the initial enrollment questionnaire) lacked information on a week-by-week basis during the first trimester. Combined exposure to more than 1 drug at any time during pregnancy was also analyzed by comparing those unexposed to any drug to those exposed to 1 drug or to 2 or more drugs. All analyses were adjusted for potential confounders as described above (in the section on covariates). We also assumed robust standard errors in all adjusted analyses to account for clustering in observations (boys) with the same mothers (n = 1715). All analyses were done separately for the 2 endpoints—cryptorchidism diagnosis and orchiopexy.
We performed secondary analyses to determine the consistency of our results when changes were made in the analytical approach. Birth weight, gestational age, and other congenital malformations are associated with cryptorchidism,25,26,31 and we assumed that these are intermediary variables rather than confounders. However, some may argue that these factors reflect the presence of other unmeasured confounders at baseline that led to the outcomes of interest. We therefore evaluated whether inclusion of these variables in the models changed the estimates. We repeated our analyses in a population of boys without other congenital malformations (n = 44,174) to evaluate potential effects on nonsyndromic cryptorchidism and to exclude observations already reported in a previous study.21 To control for confounding by indication, we fitted a model that included 3 variables describing diseases or conditions that may trigger use of NSAIDs or acetaminophen: disease in muscles and joints during pregnancy (yes/no), fever during pregnancy (yes/no), and inflammation or infection during pregnancy (yes/no). In addition to assuming robust standard errors, we performed analyses restricted to the first-born boy in the cohort (n = 45,685). Incomplete information on covariates was handled by including a “missing” category for each variable in the models to retain observations in the analysis and thus to avoid bias from exclusion due to incomplete information. We also performed analyses restricted to those with complete information on all covariates (n = 42,891) to see if this changed our estimates. Finally, we excluded a small group of mothers (n = 663) with self-reported diabetes mellitus, because this condition may act as a confounder.32 We used restriction instead of adjustment because strata with diabetic mothers were small. Statistical analysis was done using Stata 11.0 software (Statacorp, College Station, TX).
RESULTS
Of all pregnancies registered in the Danish National Birth Cohort (n = 101,091), we excluded those that did not end with at least 1 live birth (n = 6380), those with female offspring (n = 46,207), those with twin or higher multiple births (n = 997), and pregnancies where boys or mothers were not uniquely identifiable (n = 107). The remaining 47,400 mother-boy pairs were eligible for analysis. Of these, 46,500 (98%) were followed until study closure on 21 October 2009, 645 were censored due to emigration and 255 were censored because they died during the study period. Altogether, 980 boys (2.1%) were recorded in the Danish National Patient Registry with a cryptorchidism diagnosis. Of these, 565 underwent an orchiopexy. Of the mothers, 21,504 (45%) were not exposed to acetaminophen, ibuprofen, or acetylsalicylic acid during pregnancy; 22,449 (47%) were exposed some time during pregnancy to acetaminophen, 2333 (5%) to ibuprofen and 3135 (7%) to acetylsalicylic acid. Among the mothers using ibuprofen and acetylsalicylic acid during pregnancy, 57% and 50%, respectively, also used acetaminophen at some time during pregnancy. Characteristics of the study population are presented in Table 1. Maternal age, presence of a brother in the cohort, a report of fever, muscle or joint disease, inflammation or infection, and maternal smoking were all associated with use of the drugs.
Table 2 presents crude and adjusted HRs for cryptorchidism and orchiopexy according to exposure to acetaminophen, ibuprofen, and acetylsalicylic acid. Exposure to acetaminophen in both the first and second trimesters was associated with increased occurrence of a cryptorchidism diagnosis (HR = 1.33 [95% confidence interval {CI} = 1.00-1.77]) and orchiopexy (1.26 [0.86-1.84]). Exposure in all 3 trimesters also was associated with an increased (but weaker) risk of both a cryptorchidism diagnosis (1.17 [0.94-1.46]) and orchiopexy (1.06 [0.78-1.43]). Exposure within any single trimester alone was only weakly associated with cryptorchidism, if at all. Exposure within gestational weeks 8-14 (the suggested male programming window) was weakly associated with a cryptorchidism diagnosis (1.14 [0.97-1.34]) and orchiopexy (1.10 [0.89-1.36]). Exposure to ibuprofen or acetylsalicylic acid was not consistently associated with cryptorchidism.
TABLE 2: Hazard Ratios and 95% Confidence Intervals for Cryptorchidism and Orchiopexy According to Mothers' Use of Acetaminophen, Ibuprofen, and Acetylsalicylic Acid During Pregnancy, Danish National Birth Cohort, 1996–2002
Analyses of cumulative acetaminophen exposure and combined exposure to the 3 drugs are presented in Table 3. No clear dose-dependent pattern was observed, although cumulative acetaminophen exposure during pregnancy of more than 4 weeks was associated with HR point estimates above 1.0. For example, 5-8 weeks of exposure was associated with increased occurrence of a cryptorchidism diagnosis (HR = 1.32 [CI = 0.97-1.78]) and orchiopexy (1.63 [1.13-2.34]). Exposure during more than 4 weeks within the suggested male programming window was also associated with increased occurrence of a cryptorchidism diagnosis (1.38 [1.05-1.83]) and orchiopexy (1.44 [1.00-2.06]). Combined exposure to more than 1 drug did not add to the risk of cryptorchidism (Table 3).
TABLE 3: Hazard Ratios and 95% Confidence Intervals for Cryptorchidism and Orchiopexy According to Weeks of Use of Acetaminophen and Combined Exposure to Acetaminophen, Ibuprofen, and Acetylsalicylic Acid During Pregnancy, Danish National Birth Cohort, 1996–2002
We performed secondary analyses to test the validity of our analytical approach, including (1) adjustment for birth weight, gestational age, and other congenital malformations, (2) adjustment for diseases in muscles or joints, fever, or infections during pregnancy, (3) restriction to the first of brothers born in the cohort, (4) restriction to mother-boy pairs with complete information on covariates, (5) restriction to boys without other congenital malformations, and (6) exclusion of mothers with self-reported diabetes mellitus. The results of these secondary analyses were all very similar to those presented and did not alter our conclusions.
DISCUSSION
Maternal use of ibuprofen and acetylsalicylic acid was not associated with excess occurrence of cryptorchidism, but exposure to these drugs are not common among pregnant Danish women, and only crude exposure groups were available for analysis. In contrast, approximately 47% of the cohort reported use of acetaminophen, allowing analyses of timing of exposure and cumulative exposure. Overall, we observed no markedly increased occurrence of cryptorchidism with fetal acetaminophen exposure, but cumulative exposure of more than 4 weeks and exposure during the first and second trimesters was associated with increased HRs for cryptorchidism. We found no dose-response associations, which may be explained by crude dose measurements. The finding of an excess occurrence among those exposed during the suggested male programming window (gestational weeks 8-14), is consistent with studies indicating that diethylstilbestrol exposure must start before week 11 to increase the risk of cryptorchidism.33 However, too few women were exposed only during weeks 8-14 to allow for estimation of effects specifically for this time window. The associations for gestational weeks 8-14 may consequently be confounded by acetaminophen exposure during other parts of pregnancy.
It is unlikely that selection into this cohort affected the associations under study, and losses to follow-up were minimal. Only 900 (2%) boys were lost to follow-up because of death or emigration. Furthermore, previous studies have demonstrated that nonparticipation in cohort studies probably has only small effects on the internal validity.34 Exposure was assessed prospectively at each interview during pregnancy based on detailed information concerning periods of use, and included prescribed and over-the-counter use of acetaminophen, ibuprofen, and acetylsalicylic acid. There may be differential recall bias of exposures reported (retrospectively) in the interview 6 months postpartum, but this would affect only exposures late in the third trimester. The study's conclusions are unlikely to be affected by recall bias, because data for most of pregnancy (from 4 weeks prior to the last menstrual period to around gestational week 32) were collected before cryptorchidism could be recognized. Even in the data collected after recognition was possible, differential reporting of exposures by boys' cryptorchidism status is unlikely. It has been shown that the rigorous assessment of drug usage in our study cohort yields higher rates of reported use than data from prescription databases. This is not unexpected because most of these analgesics are sold over-the-counter.35 The inherent imprecision of gestational age assessment would tend to attenuate associations due to misclassification of the timing of exposure, and may lead to underestimation of effects. Any exposure misclassification by mothers regarding usage, names of drugs, and timing of exposure would also most likely lead to underestimation of effects.
Ascertainment of cryptorchidism was based on routine data from Danish nationwide registries independent of maternal exposure. To our knowledge, the validity of the cryptorchidism diagnosis in Danish registries has never been directly assessed, but orchiopexy cases encompassing both diagnosis and corrective surgery are considered highly specific. Our cases of cryptorchidism were mostly persistent, since transient cryptorchidism with spontaneous descent within 3-6 months usually is not reported to the registries. Some transient cases that reoccur as ascensus testis (recurrent cryptorchidism) were probably included given the follow-up period of our study population.29 Overall, our findings were similar for the cryptorchidism and the orchiopexy endpoints.
Women who use analgesics for an extended period of time during pregnancy may be predominantly those with a chronic disorder. Confounding by indication may be more prominent in the regular users than among infrequent users, who consume analgesics sporadically for conditions such as headache. We aimed to adjust for confounding by indication in the secondary analyses and results were essentially unchanged. However, some unadjusted or residual confounding may still explain our findings.
To our knowledge, this is the first study that aimed specifically to study associations between weak analgesics and cryptorchidism. Previous studies have mostly addressed congenital anomalies overall, using, for example, the EUROCAT classification that excludes “minor malformations” such as cryptorchidism unless they co-occur with major malformations.21,22 Animal and in vitro studies lend some support to the hypothesis under study. The COX inhibitors, acetaminophen, ibuprofen, and acetylsalicylic acid have shown endocrine-disruptive properties in the rainbow trout, affecting steroid hormone synthesis.13 Prostaglandins from the COX pathway seem to modulate testosterone production in animal Leydig cells.9–11,36,37 However, some studies support the hypothesis that COX inhibition leads to reduced testosterone production36 while others do not,9–11,37 and the net effect of COX inhibition on testicular steroid genesis is not clear. One human study in men showed that COX inhibition by acetylsalicylic acid reduced production of testosterone, 17OH-progesterone, androstenedione, and dehydroepiandrosterone in response to hCG.14 Whether this applies to other COX inhibitors and to the crucial hCG-induced testosterone production in utero remains unknown.
In conclusion, our study indicates that cumulative acetaminophen exposure of more than 4 weeks' duration, especially during the first and second trimesters, may moderately increase the occurrence of cryptorchidism. Exposure to ibuprofen and acetylsalicylic acid was not associated with cryptorchidism.
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