TY - JOUR
AU1 - Knudsen, Signe, Schöllhammer
AU2 - Bech, Bodil, Hammer
AU3 - Deleuran, Bent, Winding
AU4 - Ramlau-Hansen, Cecilia, Høst
AU5 - Arendt, Linn, Håkonsen
AB - Abstract Objectives RA and SLE are the most prevalent autoimmune rheumatic diseases affecting young women. Both diseases are characterized by systemic inflammation that may affect placental function and fetal development during pregnancy, and both diseases are associated with adverse pregnancy and child outcomes. We investigated the associations between maternal RA or SLE and the two genital malformations, cryptorchidism and hypospadias. Methods In this nationwide register-based study including all male singleton live births in Denmark from 1995 to 2016, we assessed the occurrence of cryptorchidism and hypospadias according to the prenatal disease-state of the mothers. Using Cox proportional hazards models we calculated adjusted hazard ratios, accounting for varying age at diagnosis. Results Among 690 240 boys, 1026 had a mother with RA and 352 had a mother with SLE. We found adjusted hazard ratios of 1.72 (95% CI: 1.15; 2.57) for cryptorchidism among boys born to mothers with RA and 1.46 (95% CI: 0.69; 3.06) for boys born to mothers with SLE, compared with the general population. As the number of hypospadias cases was low, multivariate analysis was not feasible. The crude hazard ratios were 0.51 (95% CI: 0.16; 1.58) and 1.00 (95% CI: 0.25; 4.03) for RA and SLE, respectively. Conclusion Boys born to mothers with RA had higher risk of cryptorchidism, compared with unexposed boys. Boys born to mothers with SLE showed a similar tendency, however with less precision of the estimate. No conclusion could be reached on the risk of hypospadias, due to the low number of events. rheumatoid arthritis, systematic lupus erythematosus and autoimmunity, pregnancy and rheumatic disease, epidemiology, reproductive Rheumatology key messages Maternal RA and SLE are associated with increased risk of cryptorchidism. Maternal preclinical RA is associated with increased risk of cryptorchidism. Introduction RA and SLE are the most prevalent autoimmune rheumatic diseases affecting women of reproductive age. The diseases are characterized by systemic inflammation with raised levels of circulating pro-inflammatory factors and autoantibodies, and placental function is known to be impaired in women with active autoimmune disease [1]. Women suffering from RA or SLE have a higher risk of adverse pregnancy outcomes such as preterm birth, low birth weight and preeclampsia [1]. Several previous studies have reported a higher overall risk of congenital malformations in children of women with RA [2, 3] and SLE [4, 5]. Only a few studies have further explored the risk of specific malformations [2, 6], but no pattern of specific malformations associated with maternal RA or SLE has been definitively established, neither have effects in the time period prior to diagnosis been examined [4]. An increasing number of children are born to mothers with RA or SLE compared with previous decades, emphasizing the importance of exploring this subject further [1, 3]. The two genital malformations cryptorchidism (undescended testis) and hypospadias (ventral displacement of the urethral opening) are among the most frequent malformations in boys [7, 8]. They arise from an imperfect fetal genital development, but the aetiology remains uncertain. Both malformations are associated with reduced fertility in adulthood, and cryptorchidism increases the risk of testicular cancer [7]. It has consistently been shown that their occurrence is associated with preterm birth and low birth weight [8, 9], suggesting there are shared causes of these adverse pregnancy outcomes and genital malformations. This has led to the hypothesis that placental dysfunction, and maternal conditions known to affect placental function, may impair fetal genital development in male offspring, causing cryptorchidism and hypospadias [8, 10], as well as preterm birth and low birth weight. To our knowledge, the risk of genital malformations in boys of mothers with RA or SLE has not previously been studied, and we aimed to study this association. Methods Study population In this nationwide, population-based study, we included all live-born singleton boys born in Denmark from 1 January 1995 to 31 December 2016, identified through the Danish Medical Birth Registry [11] and the Civil Registration System [12]. The unique central personal registry number, assigned to all Danish residents at birth or immigration, facilitated linking boys to their birth mother, and linking to more registries, at the individual level. The boys were followed until 31 December 2016. RA and SLE exposure ascertainment Information on maternal RA and SLE was extracted from the Danish National Patient Register [13], which covers all inpatient contacts to public hospitals since 1977, and outpatient contacts since 1995. As Danish public healthcare is tax-funded and free to use for all residents, the register includes the vast majority of all hospital contacts. Boys were considered exposed if the mother had at least two hospital contacts, prior to birth, with a diagnosis code of RA or SLE as defined by the International Classification of Diseases, 8th edition (ICD-8) or 10th edition (ICD-10). Maternal age at RA diagnosis was required to be ≥15 years, to avoid misclassification by accidentally including juvenile arthritis forms, as they most likely represent a separate disease subset. To account for possible effects of anti-rheumatic medication use in pregnancy, we included a preclinical RA exposure group, in a secondary analysis. Preclinical RA was defined as the mother being diagnosed with RA within 3 years after giving birth. This group of mothers is likely to have had subclinical disease activity during pregnancy [14], but is unlikely to have received anti-rheumatic treatment. This analysis was performed on a subset of the study population with a minimum of 3 years follow-up on the mother, to ensure that all had the chance to be classified as exposed. To examine whether there were different effects of RA subtypes, we also subdivided maternal RA into seropositive and seronegative RA, on the basis of ICD-10 codes. All ICD diagnosis codes are summarized in supplementary Table S1, available at Rheumatology online. Outcome ascertainment Cryptorchidism and hypospadias were classified using the Danish National Patient Register [13]. Cryptorchidism cases were defined as boys receiving an ICD-10 diagnosis of cryptorchidism at any time from birth until end of follow-up. Among boys diagnosed, we further identified those who also were registered with a surgical procedure for correctional orchidopexy, to improve the specificity. In the analyses, we studied both endpoints for cryptorchidism (i.e. cryptorchidism with surgical procedure and irrespective of surgical procedure). Hypospadias cases were defined as boys having an ICD-10 diagnosis of hypospadias from birth until end of follow-up. Statistical analyses There was no missing data on exposure or outcome, but data on one or more covariates were missing in 15.8% of subjects (when ignoring pre-pregnancy BMI, which was not available before 2004). Missing data were handled by multiple imputation, using a chained equations approach (see supplementary material section Missing Data Handling, available at Rheumatology online). Although cryptorchidism and hypospadias are congenital malformations, boys are diagnosed throughout childhood. Further, boys were followed for various follow-up times. To account for differences in follow-up time, we used Cox proportional hazards models estimating hazards ratios (HRs) with 95% CIs, with the boys’ age as the underlying time variable. RA and SLE were considered as two separate exposures, and all analyses were performed for both exposures separately (not mutually exclusive). We adjusted for maternal age, parity, educational level, pre-gestational BMI and smoking in early pregnancy, as listed in Table 1, available through the Civil Registration System, Statistics Denmark and the Medical Birth Register. We used robust standard errors to account for siblings not being independent. Boys were followed until the date of diagnosis of cryptorchidism or hypospadias, death, migration or end of follow-up (31 December 2016), whichever came first. All analyses were performed using STATA, version 11 (StataCorp.,Texas, USA). Table 1 Descriptive characteristics of 690 240 Danish boys, according to maternal RA and SLE Characteristics RA SLE Total Total, n (%) 1026 (0.15) 352 (0.05) 690 240 (100.00) Maternal age at delivery, n (%)  <25 years 77 (7.5) 24 (6.8) 94 749 (13.7)  25–29 years 278 (27.1) 101 (28.7) 234 821 (34)  30–35 years 392 (38.2) 140 (39.8) 240 526 (34.8)  >35 years 279 (27.2) 87 (24.7) 120 099 (17.4) Maternal smoking in pregnancy, n (%a)  Smoker 124 (13.1) 43 (13.9) 84 923 (14.2)  Non smoker 800 (84.7) 260 (84.1) 500 537 (83.3)  Smoking in early pregnancy 20 (2.1) 6 (1.9) 14 845 (2.5)  Missing, n (% of total) 82 (7.9) 43 (12) 89 935 (15) Maternal BMI, n (%a )  ≤18.5 kg/m2 22 (3) 11 (4.6) 16 359 (4.4)  18.6–24.9 kg/m2 447 (61.5) 150 (63.8) 234 287 (62.5)  25.0–29.9 kg/m2 151 (20.8) 47 (20.0) 78 287 (20.9)  ≥30.0 kg/m2 106 (14.6) 26 (11.1) 45 788 (12.2)  Missing, n (% of total) 300 (29.2) 118 (33.5) 315 442 (45.7) Maternal education, n (%a)  ≤9 years 154 (15.1) 65 (18.7) 101 557 (15.1)  >9 to ≤15 years 378 (37.2) 144 (41.6) 294 577 (43.7)  >15 years 484 (47.6) 137 (39.5) 278 324 (41.3)  Missing, n (% of total) 10 (1) 6 (1.7) 15 782 (2.3) Maternal nationality, n (%)  Nordic countries 975 (95) (∼90) 631 487 (91.5)  Other countries 51 (5) (∼10) 57 880 (8.4)  Missing, n (% of total) 0 NA 873 (0.1) Parity, n (%)  Nulliparous 432 (42.1) (∼46) 304 090 (44.1)  Primiparous or more 584 (56.9) (∼54) 378 994 (54.9)  Missing, n (% of total) 10 (0.97) NA 7156 (1.04) Calendar year at birth, n (%)  1995–1999 125 (12.2) 55 (15.6) 166 571 (24.2)  2000–2004 181 (17.6) 68 (19.3) 159 564 (23.1)  2005–2009 307 (29.9) 101 (28.7) 158 274 (22.9)  2010–2016 413 (40.3) 128 (36.4) 205 831 (29.8) Characteristics RA SLE Total Total, n (%) 1026 (0.15) 352 (0.05) 690 240 (100.00) Maternal age at delivery, n (%)  <25 years 77 (7.5) 24 (6.8) 94 749 (13.7)  25–29 years 278 (27.1) 101 (28.7) 234 821 (34)  30–35 years 392 (38.2) 140 (39.8) 240 526 (34.8)  >35 years 279 (27.2) 87 (24.7) 120 099 (17.4) Maternal smoking in pregnancy, n (%a)  Smoker 124 (13.1) 43 (13.9) 84 923 (14.2)  Non smoker 800 (84.7) 260 (84.1) 500 537 (83.3)  Smoking in early pregnancy 20 (2.1) 6 (1.9) 14 845 (2.5)  Missing, n (% of total) 82 (7.9) 43 (12) 89 935 (15) Maternal BMI, n (%a )  ≤18.5 kg/m2 22 (3) 11 (4.6) 16 359 (4.4)  18.6–24.9 kg/m2 447 (61.5) 150 (63.8) 234 287 (62.5)  25.0–29.9 kg/m2 151 (20.8) 47 (20.0) 78 287 (20.9)  ≥30.0 kg/m2 106 (14.6) 26 (11.1) 45 788 (12.2)  Missing, n (% of total) 300 (29.2) 118 (33.5) 315 442 (45.7) Maternal education, n (%a)  ≤9 years 154 (15.1) 65 (18.7) 101 557 (15.1)  >9 to ≤15 years 378 (37.2) 144 (41.6) 294 577 (43.7)  >15 years 484 (47.6) 137 (39.5) 278 324 (41.3)  Missing, n (% of total) 10 (1) 6 (1.7) 15 782 (2.3) Maternal nationality, n (%)  Nordic countries 975 (95) (∼90) 631 487 (91.5)  Other countries 51 (5) (∼10) 57 880 (8.4)  Missing, n (% of total) 0 NA 873 (0.1) Parity, n (%)  Nulliparous 432 (42.1) (∼46) 304 090 (44.1)  Primiparous or more 584 (56.9) (∼54) 378 994 (54.9)  Missing, n (% of total) 10 (0.97) NA 7156 (1.04) Calendar year at birth, n (%)  1995–1999 125 (12.2) 55 (15.6) 166 571 (24.2)  2000–2004 181 (17.6) 68 (19.3) 159 564 (23.1)  2005–2009 307 (29.9) 101 (28.7) 158 274 (22.9)  2010–2016 413 (40.3) 128 (36.4) 205 831 (29.8) When missing is not reported, there were no missing values. aPercentages are reported as relative percentages among the categories (for easy comparability between groups), and percentage of missing values is reported as percentage of total observations in group. NA: not available. Open in new tab Table 1 Descriptive characteristics of 690 240 Danish boys, according to maternal RA and SLE Characteristics RA SLE Total Total, n (%) 1026 (0.15) 352 (0.05) 690 240 (100.00) Maternal age at delivery, n (%)  <25 years 77 (7.5) 24 (6.8) 94 749 (13.7)  25–29 years 278 (27.1) 101 (28.7) 234 821 (34)  30–35 years 392 (38.2) 140 (39.8) 240 526 (34.8)  >35 years 279 (27.2) 87 (24.7) 120 099 (17.4) Maternal smoking in pregnancy, n (%a)  Smoker 124 (13.1) 43 (13.9) 84 923 (14.2)  Non smoker 800 (84.7) 260 (84.1) 500 537 (83.3)  Smoking in early pregnancy 20 (2.1) 6 (1.9) 14 845 (2.5)  Missing, n (% of total) 82 (7.9) 43 (12) 89 935 (15) Maternal BMI, n (%a )  ≤18.5 kg/m2 22 (3) 11 (4.6) 16 359 (4.4)  18.6–24.9 kg/m2 447 (61.5) 150 (63.8) 234 287 (62.5)  25.0–29.9 kg/m2 151 (20.8) 47 (20.0) 78 287 (20.9)  ≥30.0 kg/m2 106 (14.6) 26 (11.1) 45 788 (12.2)  Missing, n (% of total) 300 (29.2) 118 (33.5) 315 442 (45.7) Maternal education, n (%a)  ≤9 years 154 (15.1) 65 (18.7) 101 557 (15.1)  >9 to ≤15 years 378 (37.2) 144 (41.6) 294 577 (43.7)  >15 years 484 (47.6) 137 (39.5) 278 324 (41.3)  Missing, n (% of total) 10 (1) 6 (1.7) 15 782 (2.3) Maternal nationality, n (%)  Nordic countries 975 (95) (∼90) 631 487 (91.5)  Other countries 51 (5) (∼10) 57 880 (8.4)  Missing, n (% of total) 0 NA 873 (0.1) Parity, n (%)  Nulliparous 432 (42.1) (∼46) 304 090 (44.1)  Primiparous or more 584 (56.9) (∼54) 378 994 (54.9)  Missing, n (% of total) 10 (0.97) NA 7156 (1.04) Calendar year at birth, n (%)  1995–1999 125 (12.2) 55 (15.6) 166 571 (24.2)  2000–2004 181 (17.6) 68 (19.3) 159 564 (23.1)  2005–2009 307 (29.9) 101 (28.7) 158 274 (22.9)  2010–2016 413 (40.3) 128 (36.4) 205 831 (29.8) Characteristics RA SLE Total Total, n (%) 1026 (0.15) 352 (0.05) 690 240 (100.00) Maternal age at delivery, n (%)  <25 years 77 (7.5) 24 (6.8) 94 749 (13.7)  25–29 years 278 (27.1) 101 (28.7) 234 821 (34)  30–35 years 392 (38.2) 140 (39.8) 240 526 (34.8)  >35 years 279 (27.2) 87 (24.7) 120 099 (17.4) Maternal smoking in pregnancy, n (%a)  Smoker 124 (13.1) 43 (13.9) 84 923 (14.2)  Non smoker 800 (84.7) 260 (84.1) 500 537 (83.3)  Smoking in early pregnancy 20 (2.1) 6 (1.9) 14 845 (2.5)  Missing, n (% of total) 82 (7.9) 43 (12) 89 935 (15) Maternal BMI, n (%a )  ≤18.5 kg/m2 22 (3) 11 (4.6) 16 359 (4.4)  18.6–24.9 kg/m2 447 (61.5) 150 (63.8) 234 287 (62.5)  25.0–29.9 kg/m2 151 (20.8) 47 (20.0) 78 287 (20.9)  ≥30.0 kg/m2 106 (14.6) 26 (11.1) 45 788 (12.2)  Missing, n (% of total) 300 (29.2) 118 (33.5) 315 442 (45.7) Maternal education, n (%a)  ≤9 years 154 (15.1) 65 (18.7) 101 557 (15.1)  >9 to ≤15 years 378 (37.2) 144 (41.6) 294 577 (43.7)  >15 years 484 (47.6) 137 (39.5) 278 324 (41.3)  Missing, n (% of total) 10 (1) 6 (1.7) 15 782 (2.3) Maternal nationality, n (%)  Nordic countries 975 (95) (∼90) 631 487 (91.5)  Other countries 51 (5) (∼10) 57 880 (8.4)  Missing, n (% of total) 0 NA 873 (0.1) Parity, n (%)  Nulliparous 432 (42.1) (∼46) 304 090 (44.1)  Primiparous or more 584 (56.9) (∼54) 378 994 (54.9)  Missing, n (% of total) 10 (0.97) NA 7156 (1.04) Calendar year at birth, n (%)  1995–1999 125 (12.2) 55 (15.6) 166 571 (24.2)  2000–2004 181 (17.6) 68 (19.3) 159 564 (23.1)  2005–2009 307 (29.9) 101 (28.7) 158 274 (22.9)  2010–2016 413 (40.3) 128 (36.4) 205 831 (29.8) When missing is not reported, there were no missing values. aPercentages are reported as relative percentages among the categories (for easy comparability between groups), and percentage of missing values is reported as percentage of total observations in group. NA: not available. Open in new tab For sensitivity analyses, we repeated the main analyses with restriction to births after 2003 to evaluate the influence of the imputed BMI values. Furthermore, we performed complete case analyses to compare the multiple imputation-based results with complete case analysis and the crude results. Finally, we repeated the analyses without adjusting for pre-gestational BMI as it could be viewed as a mediator, rather than a confounding risk factor, dependent on the temporality of events. Gestational age and birth weight were not included as potential confounders, due to the temporality of these events (i.e. a malformation is present before a premature birth). The study was approved by the Danish Data Protection Agency (No. 2015-57-0002). Data were stored at the secure platform with Statistics Denmark and according to their rules and regulations; we were not allowed to report results concerning fewer than five individuals in each stratum. Results The final study population consisted of 690 240 boys with an average follow-up time of 10.7 years (s.d. 6.5 years). Approximately 0.4% of boys died during follow-up. In total, 1026 (0.15%) boys were born to mothers with RA and 352 (0.05%) boys were born to mothers with SLE. Mothers with RA or SLE were slightly older at delivery, but had similar educational level, parity and nationality as unaffected mothers. They were less often smokers, and mothers with RA had slightly higher pre-pregnancy BMIs (Table 1). Exposed boys were more often born in the later years of the inclusion period (Table 1). Mean gestational age was 3 days shorter among RA-exposed and 12 days shorter among SLE-exposed boys, compared with the population average. The percentage of very premature boys was 1.1% for RA exposed, 5.4% for SLE exposed and 0.7% for the total population (Table 2). Table 2 Birth characteristics of 690 240 Danish boys, according to maternal RA and SLE. RA SLE Total Total, n 1026 352 690 240 Gestational age  Gestational days, mean (s.d.) 275.7 (14.8) 266.2 (22.5) 278.3 (13.0)  Preterm <37 weeks, n (%) 89 (8.6) 66 (18.7) 35 764 (5.2)  Very preterm <32 weeks, n (%) 11 (1.1) 19 (5.4) 5067 (0.7)  Missing, n (%) 9 (0.8) <5 (<1) 6885 (0.9) Birth weight  Weight in g, mean (s.d.) 3465.4 (620.5) 3096.3 (794.5) 3581.5 (577.5)  Missing, n (%) 9 (0.8) 5 (1.4) 8753 (1.3) Placental weight  Weight in g, mean (s.d.) 653.4 (149.9) 594 (163.4) 673.8 (149.7)  Missing, n (%) 75 (7.4) 44 (12.5) 92 371 (13.4) RA SLE Total Total, n 1026 352 690 240 Gestational age  Gestational days, mean (s.d.) 275.7 (14.8) 266.2 (22.5) 278.3 (13.0)  Preterm <37 weeks, n (%) 89 (8.6) 66 (18.7) 35 764 (5.2)  Very preterm <32 weeks, n (%) 11 (1.1) 19 (5.4) 5067 (0.7)  Missing, n (%) 9 (0.8) <5 (<1) 6885 (0.9) Birth weight  Weight in g, mean (s.d.) 3465.4 (620.5) 3096.3 (794.5) 3581.5 (577.5)  Missing, n (%) 9 (0.8) 5 (1.4) 8753 (1.3) Placental weight  Weight in g, mean (s.d.) 653.4 (149.9) 594 (163.4) 673.8 (149.7)  Missing, n (%) 75 (7.4) 44 (12.5) 92 371 (13.4) Open in new tab Table 2 Birth characteristics of 690 240 Danish boys, according to maternal RA and SLE. RA SLE Total Total, n 1026 352 690 240 Gestational age  Gestational days, mean (s.d.) 275.7 (14.8) 266.2 (22.5) 278.3 (13.0)  Preterm <37 weeks, n (%) 89 (8.6) 66 (18.7) 35 764 (5.2)  Very preterm <32 weeks, n (%) 11 (1.1) 19 (5.4) 5067 (0.7)  Missing, n (%) 9 (0.8) <5 (<1) 6885 (0.9) Birth weight  Weight in g, mean (s.d.) 3465.4 (620.5) 3096.3 (794.5) 3581.5 (577.5)  Missing, n (%) 9 (0.8) 5 (1.4) 8753 (1.3) Placental weight  Weight in g, mean (s.d.) 653.4 (149.9) 594 (163.4) 673.8 (149.7)  Missing, n (%) 75 (7.4) 44 (12.5) 92 371 (13.4) RA SLE Total Total, n 1026 352 690 240 Gestational age  Gestational days, mean (s.d.) 275.7 (14.8) 266.2 (22.5) 278.3 (13.0)  Preterm <37 weeks, n (%) 89 (8.6) 66 (18.7) 35 764 (5.2)  Very preterm <32 weeks, n (%) 11 (1.1) 19 (5.4) 5067 (0.7)  Missing, n (%) 9 (0.8) <5 (<1) 6885 (0.9) Birth weight  Weight in g, mean (s.d.) 3465.4 (620.5) 3096.3 (794.5) 3581.5 (577.5)  Missing, n (%) 9 (0.8) 5 (1.4) 8753 (1.3) Placental weight  Weight in g, mean (s.d.) 653.4 (149.9) 594 (163.4) 673.8 (149.7)  Missing, n (%) 75 (7.4) 44 (12.5) 92 371 (13.4) Open in new tab During follow-up, 17 494 (2.53%) boys were diagnosed with cryptorchidism with a mean age at time of diagnosis of 3.3 years (s.d. 3.0 years). Of these, 9546 (1.38% of all live born boys) also underwent corrective surgery. Of the 1026 boys exposed to RA, 40 (3.9%) boys were diagnosed with cryptorchidism, of which 24 (2.3%) underwent corrective surgery. Maternal RA was associated with a higher rate of cryptorchidism: when assessing cryptorchidism that persisted until corrective surgery, the adjusted HR was 1.72 (95% CI: 1.15; 2.57), and when including all diagnosed with cryptorchidism regardless of surgery, the HR was 1.53 (95% CI: 1.12; 2.08) (Table 3). Among the mothers with RA, 597 mothers were classified as having seropositive RA and 350 with seronegative RA, on the basis of ICD codes (the remaining 79 could not be categorized). The boys born to mothers with seropositive RA had a higher risk of being diagnosed with cryptorchidism than those exposed to seronegative maternal RA (Fig. 1). Fig. 1 Open in new tabDownload slide HRs for cryptorchidism in maternal RA-exposed compared with unexposed Danish boys, born between 1995 and 2016 Reference group for all HRs are ‘no maternal RA’. HR: hazard ratio. Fig. 1 Open in new tabDownload slide HRs for cryptorchidism in maternal RA-exposed compared with unexposed Danish boys, born between 1995 and 2016 Reference group for all HRs are ‘no maternal RA’. HR: hazard ratio. Table 3 HRs for cryptorchidism according to maternal RA and SLE among Danish boys from 1995 to 2016 Cryptorchidism with corrective surgery Cryptorchidism, anya Total (n) Cases (n) cHR aHR (95% CI) Cases (n) cHR aHR (95% CI) RA  Unexposed 689 214 9522 1 1 17 454 1 1  Exposed 1026 24 1.83 1.72 (1.15, 2.57) 40 1.62 1.53 (1.12, 2.08) SLE  Unexposed 689 888 9539 1 1 17 479 1 1  Exposed 352 7 1.54 1.46 (0.69, 3.06) 15 1.80 1.68 (1.01, 2.78) Cryptorchidism with corrective surgery Cryptorchidism, anya Total (n) Cases (n) cHR aHR (95% CI) Cases (n) cHR aHR (95% CI) RA  Unexposed 689 214 9522 1 1 17 454 1 1  Exposed 1026 24 1.83 1.72 (1.15, 2.57) 40 1.62 1.53 (1.12, 2.08) SLE  Unexposed 689 888 9539 1 1 17 479 1 1  Exposed 352 7 1.54 1.46 (0.69, 3.06) 15 1.80 1.68 (1.01, 2.78) a Includes all ICD-10 diagnoses of cryptorchidism, regardless of subsequent surgical treatment. aHR: hazard ratio adjusted for birth year and maternal factors: age at time of birth, educational level, smoking status during pregnancy, pre-pregnancy BMI, nationality and parity; cHR: crude hazard ratio; ICD-10: International Classification of Diseases, 10th revision. Open in new tab Table 3 HRs for cryptorchidism according to maternal RA and SLE among Danish boys from 1995 to 2016 Cryptorchidism with corrective surgery Cryptorchidism, anya Total (n) Cases (n) cHR aHR (95% CI) Cases (n) cHR aHR (95% CI) RA  Unexposed 689 214 9522 1 1 17 454 1 1  Exposed 1026 24 1.83 1.72 (1.15, 2.57) 40 1.62 1.53 (1.12, 2.08) SLE  Unexposed 689 888 9539 1 1 17 479 1 1  Exposed 352 7 1.54 1.46 (0.69, 3.06) 15 1.80 1.68 (1.01, 2.78) Cryptorchidism with corrective surgery Cryptorchidism, anya Total (n) Cases (n) cHR aHR (95% CI) Cases (n) cHR aHR (95% CI) RA  Unexposed 689 214 9522 1 1 17 454 1 1  Exposed 1026 24 1.83 1.72 (1.15, 2.57) 40 1.62 1.53 (1.12, 2.08) SLE  Unexposed 689 888 9539 1 1 17 479 1 1  Exposed 352 7 1.54 1.46 (0.69, 3.06) 15 1.80 1.68 (1.01, 2.78) a Includes all ICD-10 diagnoses of cryptorchidism, regardless of subsequent surgical treatment. aHR: hazard ratio adjusted for birth year and maternal factors: age at time of birth, educational level, smoking status during pregnancy, pre-pregnancy BMI, nationality and parity; cHR: crude hazard ratio; ICD-10: International Classification of Diseases, 10th revision. Open in new tab In the secondary analysis including 593 618 boys, we explored the effects of maternal preclinical RA. In this subpopulation, 865 boys were exposed to pre-existing maternal RA and 481 boys were exposed to preclinical maternal RA, i.e. their mothers were diagnosed with RA within 3 years after delivery. Both exposure categories were included and compared in the same analysis. The risk of cryptorchidism was almost as high for those exposed to preclinical RA as to pre-existing RA (Fig. 1), with an HR of 1.72 (95% CI: 0.99; 2.97) compared with 1.81 (95% CI: 1.21; 2.70) (for cryptorchidism with surgery). Of the 352 boys exposed to SLE, 15 boys (4.3%) were diagnosed with cryptorchidism, and 7 boys (2.0%) underwent corrective surgery (Table 3). Boys born to mothers with SLE had a higher risk of cryptorchidism than unexposed boys; the HR for cryptorchidism that persisted until surgery was 1.46 (95% CI: 0.69; 3.06), and 1.68 (95% CI: 1.01, 2.78) for cryptorchidism diagnosis irrespective of surgery. The sensitivity analyses performed showed results consistent with the main analyses. First, restricting to births after 2003 only slightly enhanced the associations (supplementary Table S2, available at Rheumatology online). Secondly, the complete case analyses yielded similar measures of association, slightly strengthening the association (supplementary Table S2, available at Rheumatology online). Finally, removing pre-gestational BMI from the model did not markedly change results (supplementary Table S2, available at Rheumatology online). During follow-up, 4011 boys were diagnosed with hypospadias (0.58%) with a mean age at time of diagnosis of 1.2 years (s.d. 2.3). The crude HR was 0.51 (95% CI: 0.16; 1.58) for those exposed to RA, and 1.01 (95% CI: 0.25; 4.02) for SLE. With five or fewer cases of hypospadias among boys exposed to RA or SLE, multivariable analyses were unfeasible. Discussion This large nationwide study of 690 240 boys found a higher risk of cryptorchidism among boys exposed to maternal RA or SLE in utero. The risk was highest among those born to mothers with seropositive RA, compared with seronegative RA. Furthermore, boys born to mothers with preclinical RA also faced a higher risk of cryptorchidism. The low number of boys with hypospadias exposed to RA or SLE meant that no conclusion for this association could be made. This study has several strengths. The use of the complete Danish nationwide registers enabled us to study our hypothesis in a large study population, including many exposed individuals. The registers’ minimal loss to follow-up makes selection bias due to sampling or retention unlikely, and the quality of information is generally high [13]. Data on maternal disease and covariates were recorded before knowledge on outcome, making differential misclassification unlikely. On the other hand, there is a risk that maternal disease influences the rate at which boys are examined for, and thus diagnosed with, congenital malformations. However, the proportionality of the hazards curves were visually examined and did not point towards such a detection bias (data not shown). Although we accounted for several potential confounders, we cannot rule out unknown or residual confounding. Information on medication was unavailable, therefore we cannot distinguish between the effects of the disease per se and the possible effect of medications, and such associations need to addressed in further studies. However, we expect the preclinical RA mothers would not have received any specific anti-rheumatic treatment, and consider this group a quasi-control group for the effect of treatment. The higher risk of cryptorchidism among their offspring compared with women without RA may suggest that the underlying immunological activity of the disease itself increases the risk, but it warrants further investigation. Unfortunately, information on clinical and biochemical factors such as DAS and aPL status were not available for this study. Though we consider these factors to be likely effect modifiers, this will have to be investigated in future studies. Preterm birth and low birth weight are known to be associated with cryptorchidism and hypospadias [8, 9]. Hypospadias is a malformation occurring in in first trimester; thus, preterm birth cannot cause hypospadias. On the other hand, preterm birth may result in cryptorchidism, as testicular descent is a longer process ending around gestational age 30–35 weeks. Furthermore, RA and SLE both increase the risk of prematurity, thus, in the association between RA or SLE and cryptorchidism, gestational age and birth weight are intermediate factors. We did not adjust for or stratify on these factors, as conditioning on intermediate factors could give rise to bias. Preterm birth is caused by several heterogeneous conditions and factors, and by adjusting, collider-stratification bias is known to occur, with an unpredictable direction of the bias caused [15, 16]. We cannot rule out that the increased rate of cryptorchidism among exposed boys is in part mediated by premature birth. In our data, the majority of RA- or SLE-exposed boys with cryptorchidism were neither premature nor very premature, and the correlation between prematurity and cryptorchidism was the same among exposed and unexposed boys (data not shown due to small numbers). To our knowledge, this is the first study on the association between maternal RA or SLE and the two genital malformations, cryptorchidism and hypospadias. In 2010, Nørgaard et al. performed a large Danish and Swedish study, using register-based data from 1994 to 2006. They found a 30% higher risk of congenital malformations overall among children exposed to maternal RA, and those exposed to seropositive RA had the highest risks, similar to our findings. They found that the highest risks were for cleft lip/palate anomalies, but no increased risk for urinary tract defects when studying all types, and both sexes, in combination [2]. Recently, in a population-based US cohort study including 6068 births exposed to maternal RA, Aljary et al. found a 2-fold higher risk of congenital malformations overall, but with no description of specific types of malformations, and preclinical RA was not included [3]. In 2017, another US study by Howley et al. studied the combined exposure of any maternal systemic autoimmune disease (with RA and SLE comprising the largest groups) and found no association with hypospadias [6], which is in accordance with our current findings. Furthermore, for SLE specifically, Bundhun et al. performed a meta-analysis in 2017, including three studies with >900 SLE pregnancies in total, and found an overall risk ratio for congenital malformations of 2.63 (95% CI: 1.93; 3.58) [4], but with no distinction between types of malformations. To the best of our knowledge, no previous studies have studied the association between SLE and the two genital malformations, cryptorchidism and hypospadias. Several causal mechanisms have been hypothesized to explain the seemingly higher risk of congenital malformations among children born of mothers with RA and SLE. First, placental function may be compromised when maternal inflammatory activity causes placental thrombosis and inflammation [1, 17]. Second, circulating autoantibodies are known to cross the blood–placenta barrier in pregnancy [1], but the precise effects on the fetus vary with the specific antibody affinity. With relation to our findings, citrullination is known to be important for the development of the fetus, and we observed the highest HR for cryptorchidism among those with seropositive mothers, including positivity for ACPA. Third, the metabolism of sex hormones is known to be different in conditions with raised inflammatory levels due to increased aromatase activity [1], the latter mechanism possibly affecting genital development of male fetuses, a sex-hormone dependent process. The sex differentiation of the embryo begins at gestational week 5 and the urethra is fully formed by the end of the first trimester, while the testis will usually complete descension around week 31. Any causal factors leading to one of these malformations must therefore be present during these time windows to affect the development of either condition. In conclusion, this large nationwide study found that boys born to mothers with RA or SLE had higher risk of cryptorchidism. The risk was comparable among boys exposed to preclinical RA, indicating that RA treatment may not be the underlying cause. This supports the hypothesis that maternal RA and SLE can affect the fetus in utero, but the potential specific biological pathways must be explored in future studies. Disclosure statement: The authors have declared no conflicts of interest. Funding: This work was supported by Aarhus University, the Danish Rheumatism Association and the Karen Elise Jensen foundation. 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TI - Maternal rheumatoid arthritis and systemic lupus erythematosus and risk of cryptorchidism and hypospadias in boys: a Danish nationwide study
JF - Rheumatology
DO - 10.1093/rheumatology/kez538
DA - 2004-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/maternal-rheumatoid-arthritis-and-systemic-lupus-erythematosus-and-eEfn0ro2bp
SP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -