Maternal Cigarette Smoking During Pregnancy and Genital Anomalies in Boys: A Register-Based Cohort and Sibling-Matched Design Study

Abstract

Purpose Cryptorchidism and hypospadias share several prenatal risk factors. However, in published studies, boys exposed to cigarette smoking during pregnancy have a higher risk of cryptorchidism and a lower risk of hypospadias. Using Danish register-based data, we revisited these findings with a cohort and sibling-matched design to investigate the potential effect of shared time-stable factors. Patients and Methods For the cohort study, we included 823,670 live-born, singleton boys born from 1991 to 2016. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models for each genital anomaly according to maternal cigarette smoking during pregnancy. For the sibling-matched design, we included 399,258 brothers and used a stratified Cox regression model creating family-adjusted results. Results In the cohort study, we found a higher risk of cryptorchidism (aHR = 1.18, 95% CI: 1.12, 1.24) and a lower risk of hypospadias (aHR = 0.84, 95% CI: 0.76, 0.93) when comparing boys exposed to cigarette smoking with non-exposed, and for increasing numbers of cigarettes smoked. In comparison, the sibling-matched analyses suggested a slightly weaker association for cryptorchidism and an association of similar magnitude for hypospadias, both in the same direction as in the cohort study. Conclusion Shared, familial confounding does not seem to explain earlier findings of higher risk of cryptorchidism and lower risk of hypospadias.

Maternal Exposure to Cigarette Smoke during Pregnancy and Testicular Cancer in Offspring: A Systematic Review and Meta-Analysis

“…Although our systematic review did not provide substantial evidence into an association between maternal exposure to cigarette smoking during pregnancy and testicular cancer, it remains uncertain whether our overall results are due to a lack of an association or perhaps due to the methodological limitations consistently observed across the included publications. Intriguingly, previous studies have found a link between maternal smoking during pregnancy and a higher risk of other parameters of male reproductive health, hereunder cryptorchidism [ 43 , 44 ], reduced sperm quality [ 45 , 46 , 47 ] and hypospadias [ 48 , 49 ], but also with contradictory results [ 44 , 50 , 51 ]. Nonetheless, cigarette smoke is known to contain several carcinogenic compounds [ 52 ] and components hereof, such as nicotine, have the ability to cross the placental barrier to the fetus [ 53 ].…”

Parental smoking and risk of hypospadias: An updated meta-analysis of observational studies

“…42 studies, 9 studies, and 3 studies reported maternal active smoking, paternal smoking, and maternal passive smoking, respectively. 35 (79.5%) of the 44 papers included in this study employed a casecontrol design (1,9,10,13,14,20,22,27,30,, whereas 9 (20.5%) employed a cohort study design (25,32,34,(62)(63)(64)(65)(66)(67).…”

Meconium Concentrations of Pesticides and Risk of Hypospadias: A Case–Control Study in Brittany, France

“…35 We did not observe other potential risk factors, such as maternal smoking or paracetamol or other analgesics intake during pregnancy. [36][37][38] The role of maternal smoking is still debated, as some recent studies have actually shown a lower risk of hypospadias, 35,39 whereas others have reported a higher risk. 40 Concerning paracetamol intake during pregnancy, the results of previous studies are inconsistent, with some studies having found an association with hypospadias, 36 whereas others have not.…”

“…In addition, paternal smoking was preferred to maternal smoking whose use as a risk factor for hypospadias has been challenged in the literature. 19,35,39,40 We then added maternal educational level into our multivariable model as a proxy for unmeasured socioeconomic levels to help control for a possible participation bias. Last, we decided not to adjust for preterm birth and the small-for-gestational-age (SGA) status because we suspected these characteristics to share common a cause with hypospadias.…”

“…We performed descriptive statistics and unconditional logistic regression models, minimally adjusted for district and birthyear strata. 29 We identified factors associated with the risk of hypospadias a priori from a literature review, 19,[30][31][32][33][34][35][36][37][38][39][40][41][42] ; they are described in Table 1. Among these, medication intake during pregnancy and the month before conception were reported by mothers in the questionnaire and were thoroughly reviewed, combined with the available data in the medical reports, and classified into subgroups of interest.…”