Association between parental autoimmune disease and childhood atopic dermatitis varied by sex: a nationwide case–control study

doi:10.21203/rs.3.rs-2247661/v1

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Association between parental autoimmune disease and childhood atopic dermatitis varied by sex: a nationwide case–control study

https://doi.org/10.21203/rs.3.rs-2247661/v1

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Atopic dermatitis(AD) is a common inflammatory skin disorder induced by dysfunction of immune suppression, which resembles the mechanism of autoimmune diseases. To explore the association between autoimmune diseases and AD in their children, we linked the birth data from National Birth Registry with National Health Insurance Research Database. Demographic characteristics from 1174,941 parent-child linkages were obtained. There were 312,329 children diagnosed with AD before 5 years old, and they would be compared with the other 862,612 children without AD in the control group. Conditional logistic regression was utilized to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). After adjusting infant’s characteristics, perinatal factors, and other parental diseases, the odds ratio of parental rheumatoid arthritis(RA) was 2.269 (95% CI 1.333–3.861) and parental psoriasis was1.610 (95% CI, 1.094–2.369). Parental allergic diseases such as AD (aOR 2.071, 95% CI 1.952–2.198) and asthma (aOR 1.494, 95% CI 1.400-1.594) were also significant predictors for childhood AD. The subgroup analysis showed significant difference between children’s sex. Parental RA (aOR 3.070, 95% CI, 1.532–6.154) was crucial for boys, while parental psoriasis (aOR 1.945, 95% CI, 1.129–3.350)was a risk factor for girls.

In conclusion, parental autoimmune diseases were found to be related to AD in their children before 5 years old. Additionally, there were different risk factors for AD between children’s sex.

Autoimmune disease

atopic dermatitis

rheumatoid arthritis

psoriasis

sex effect

Atopic dermatitis (AD), also called atopic eczema, is one of the most common chronic inflammatory skin disease. It affects 15–20% of the world's population, including 20% of children and up to 3% of adults.¹ Moreover, AD can induce subsequent allergic diseases such as allergic rhinitis and asthma within children, which is often referred to as the concept of “allergic march”.² The intense itching and skin manifestations in AD often result in insomnia and poor school or work performance, which showed that AD affected not only child development but also their caregivers’ quality of life.

AD is a multifactorial disease presenting with different endophenotypes.³ These variable risk factors includes parental systemic diseases, perinatal factors, family allergic history and parental autoimmune diseases.^4–6 Previous studies have proved that more mothers to children with AD received therapy of autoimmune diseases than mothers to normal children.⁶ On the other hands, both maternal and paternal autoimmune diseases may give rise to the occurrence of allergic diseases in their children.^6–8

Genes play an important role in linking AD and autoimmune diseases. The commonality of these two diseases based on the dysfunction of immune suppression, and the mechanism of which could be interpreted by the overlapping genetic loci, molecular pathway and disease-implicated cell type.⁹ Further study was conducted to figure out the genetic effect on specific autoimmune diseases and allergy. It has been discovered that there are many overlapping regions in the loci of AD and psoriasis, such as chromosome 1q12, 17q25, and 20p12.¹⁰ And the variants genes on 5p13.2 was noted within patients with either AD or multiple sclerosis, where IL7 receptor, key mediator of T-cell-driven autoimmunity, was encoded.¹¹

All of the aforementioned research suggested that parental autoimmune diseases are associated with allergic disease in their offspring; however, they did not show the common effect on their offspring when both paternal and maternal autoimmune diseases were present. We also wonder that whether parental autoimmune diseases will lead to different outcomes between male and female children. The present study is a population-based case-control study using data from the Taiwan National Health Insurance Research Database (NHIRD) and perinatal data in the National Birth Registry.

Data source

In this study, we linked perinatal data from the National Birth Registry (2006–2012) with National Health Insurance Research Database (2003–2017) to obtain independently paired parent–child linkages and associated demographic data. Taiwan’s National Health Insurance (NHI) was established in 1995 and covered up to 99.99% of Taiwan’s population. The NHIRD was released for research purposes and thoroughly provided population-based evidence to support clinical decisions. The NHIRD comprised comprehensive demographic characteristics, clinic visits, hospitalization dates, disease diagnosis codes, procedure codes, prescription codes and medical costs for reimbursement. This study was approved by the Institutional Review Board of The Institutional Review Board of Chung Shan Medical University Hospital in Taiwan. Need for informed consent was waived because the data we used was comprised of a de-identified secondary data set which had been released for research purposes and analyzed anonymously.

Study Population

The selection process of the study population is shown in Fig. 1. There were 1,337,660 infants born from 2006 to 2012 in the record of National Birth Registry. To ensure each parent-child linkage is independent, we excluded infants from multiple birth to avoid correlated linkages between twins. We also excluded stillbirth (n = 438), missing birth data from NHIRD (n = 40246), observations which were less than five years (n = 3445), and children to mothers with foreign nationalities (n = 80295). Lastly, the children who received a diagnosis of AD (ICD-9-CM code 691) before their 5th birthday would be identified because the prevalence of AD would reach the peak within the interval of 0–5 years old in the progression of allergic march.^{2 12} Subjects with AD were defined as having at least three ambulatory visits or one hospital admission with a diagnosis of ICD-9-CM code 691.

A total of 1,174,941 parent-child linkages were included in the study population, and 312,329 (2.98%) of children developed AD prior to age 5.

Parental Exposures And Baseline Characteristics

Paternal and maternal influences are important predictors for subsequent AD in their offspring. The perinatal data including infants’ sex, birth weight, gestational week, mode of delivery and parental age at delivery may also have an effect. The other parental comorbidities perceived as confounding factors were preeclampsia(ICD-9-CM code 642 or 760.0), gestational diabetes mellitus(ICD-9-CM code 648.0, 648.8 or 775.0), cervical incompetence(ICD-9-CM code 654.5), rheumatoid arthritis(RA, ICD-9-CM code 714.0), systemic lupus erythematosus (SLE, ICD-9-CM code 710.0), Sjogren’s syndrome(ICD-9-CM code 710.2), ankylosing spondylitis(AS,ICD-9-CM code720.0), psoriasis(ICD-9-CM code 696.0, 696.1), anemia(ICD-9-CM code 285.9), hypertension(ICD-9-CM code 401–405), diabetes mellitus(ICD-9-CM code 250), chronic obstructive pulmonary disease(COPD,ICD-9-CM code490-492, 493–496), hyperthyroidism(ICD-9-CM code 240.9), sleep apnea(ICD-9-CM code 327.2), asthma(ICD-9-CM code 493) and AD(ICD-9-CM code 691). The diagnostic record of these diseases were obtained from the NHI database and was included only if the diagnosis was within 3 years before the delivery.

Statistical analysis

For all baseline characteristics, means and standard deviations (SD) were calculated for all continuous variables, while counts and proportions were calculated for categorical variables. The chi-squared test was used for category variables and t-test for continuous variables. A conditional logistical regression model was conducted to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) after adjusting for relevant covariates. All statistical analysis was conducted using Statistical Analysis Software (SAS) version 9.4 (SAS System for Windows) and SPSS (version 20; SPSS Inc., Chicago, IL). A p-value less than 0.05 was considered statistically significant.

Demographic Characteristic And Percentage Of Comorbidities

Table 1 gives the baseline characteristics of 1,174,941 parent–child linkages. A higher percentage of parental autoimmune diseases was observed in the AD group rather than in the control group. Additionally, parental allergic diseases were more common in the AD group with a percentage of parental AD and asthma of 0.45% and 0.61%, respectively. This represented the differences from the control group. (Supplementary Table 1 and Supplementary Table 2)

Table 1

The baseline characteristic between control group and AD group.
	Control group (N = 862612)	AD group (N = 312329)
Perinatal outcomes
Infant’s sex
Male	447677(51.90%)	164430(52.65%)
Female	414935(48.10%)	147899(47.35%)
Birth weight, gram
< 2500	52500(6.09%)	18595(5.95%)
2500–3499	672321(77.94%)	244073(78.15%)
>=3500	137791(15.97%)	49661(15.90%)
Gestational weeks
Preterm (< 37 weeks)	27383(3.17%)	9547(3.06%)
Full-term (37–41 weeks)	807357(93.59%)	293112(93.85%)
Post-term ( > = 41 weeks)	27872(3.23%)	9670(3.10%)
Mode of delivery
Vaginal delivery	563465(65.32%)	199069(63.74%)
Cesarean delivery	295408(34.25%)	113260 (36.26%)
Maternal age at delivery
< 30	365096(42.32%)	126788(40.59%)
30–39	475599(55.13%)	178473(57.14%)
40–49	21901(2.54%)	7058(0.24%)
>=50	16(< 0.01%)	10(< 0.01%)
Obstetric complications
Preeclampsia	24527(2.84%)	9068(2.90%)
GDM	61575(7.14%)	25881(8.29%)
CI	1326(0.01%)	559(0.18%)
Autoimmune diseases
RA
Maternal*	2564(0.30%)	1151(0.37%)
Paternal*	1930(0.22%)	813(0.26%)
Both^α	30(< 0.01%)	25(< 0.01%)
SLE
Yes(Maternal)	2332(0.27%)	1028(0.33%)
SS
Maternal	6663(0.77%)	2933(0.94%)
Paternal	2860(0.33%)	1199(0.38%)
Both	383(0.04%)	163(0.05%)
AS
Maternal	1507(0.17%)	729(0.23%)
Paternal	5244(0.61%)	2292(0.73%)
Both	35(< 0.01%)	15(< 0.01%)
Psoriasis
Maternal	2890(0.34%)	1315(0.42%)
Paternal	3867(0.45%)	1585(0.51%)
Both	70(< 0.01%)	41(0.01%)
Systemic diseases
Anemia
Maternal	117099(13.57%)	43819(14.03%)
Paternal	15481(1.79%)	5859(1.88%)
Both	10557(1.22%)	4190(1.34%)
HTN
Maternal	12650(1.47%)	4926(1.58%)
Paternal	31873(3.69%)	12949(4.15%)
Both	1038(0.12%)	471(0.15%)
DM
Maternal	25933(3.01%)	10419(3.34%)
Paternal	13728(1.59%)	5574(1.78%)
Both	948(0.11%)	468(0.15%)
COPD
Maternal	13371(1.55%)	5782(1.85%)
Paternal	18302(2.12%)	7774(2.49%)
Both	1618(0.19%)	707(0.23%)
Hyperthyrodism
Maternal	21107(2.45%)	9218(2.95%)
Paternal	5201(70.38%)	2189(0.70%)
Both	261(0.60%)	111(0.03%)
OSA
Maternal	1209(0.14%)	569(0.18%)
Paternal	6164(0.71%)	2763(0.88%)
Both	69(< 0.01%)	18(< 0.01%)
Allergic diseases
Asthma
Maternal	25763(2.99%)	11888(3.81%)
Paternal	22425(2.60%)	9755(3.12%)
Both	2645(0.31%)	1410(0.45%)
AD
Maternal	64272(7.45%)	33044(10.58%)
Paternal	13599(1.58%)	6337(2.03%)
Both	2639(0.31%)	1906(0.61%)
Abbreviation: GDM, gestational diabetes mellitus; CI, cervical incompetence; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjogren’s syndrome; AS, ankylosing spondylitis; HTN, hypertension; DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; OSA, obstructive sleep apnea; AD, atopic dermatitis *Maternal or paternal comorbidities were identified within 3 years before delivery date. ^α ”Both” means both father and mother were diagnosed with the diseases mentioned in the column of “variables”.

Comparison Of Adjusted Odds Ratios Of Parental Diseases Between Ad Group And Control Group

Table 2 showed the multivariate logistical regression analysis. In conditional logistic regression analysis, the following diseases were associated with a higher risk of AD development: parental RA (aOR 2.269, 95% CI 1.333–3.861), parental psoriasis (aOR 1.610, 95% CI 1.094–2.369), parental AD (aOR 2.071, 95% CI 1.952–2.198), parental asthma (aOR 1.494, 95% CI 1.400-1.594), and diabetes mellitus (aOR 1.358, 95% CI 1.216–1.518).

Table 2

Adjusted odds ratios of risk factors for childhood AD by using multivariate logistical regression analysis
	The parental diseases existed in
Parental diseases	Neither	Only maternal	Only paternal	Both
Obstetric complications ^β
Preeclampsia	Ref	1.001(0.977–1.027)
GDM	Ref	1.164(1.146–1.181)
CI	Ref	1.168(1.058–1.290)
Autoimmune disease
RA	Ref	1.212(1.131-1.300)	1.153(1.062–1.252)	2.269(1.333–3.861)
SLE ^γ	Ref	1.177(1.093–1.267)	Nil	Nil
SS	Ref	1.181(1.130–1.234)	1.127(1.053–1.206)	1.140(0.949–1.369)
AS	Ref	1.300(1.189–1.420)	1.187(1.130–1.247)	1.152(0.629–2.111)
Psoriasis	Ref	1.243(1.164–1.327)	1.118(1.055–1.186)	1.610(1.094–2.369)
Systemic diseases
Anemia	Ref	1.030(1.018–1.043)	1.042(1.010–1.074)	1.090(1.051–1.130)
HTN	Ref	1.066(1.030–1.102)	1.115(1.092–1.139)	1.259(1.128–1.404)
DM	Ref	1.105(1.079–1.131)	1.116(1.081–1.152)	1.358(1.216–1.518)
COPD	Ref	1.186(1.150–1.224)	1.170(1.138–1.201)	1.213(1.110–1.325)
Hyperthyroidism	Ref	1.187(1.158–1.217)	1.148(1.091–1.207)	1.164(0.932–1.454)
OSA	Ref	1.265(1.145–1.398)	1.208(1.154–1.264)	0.700(0.417–1.178)
Allergic disease
Asthma	Ref	1.286(1.258–1.315)	1.211(1.182–1.241)	1.494(1.400-1.594)
AD	Ref	1.474(1.454–1.495)	1.328(1.288–1.369)	2.071(1.952–2.198)
^βThe ORs of Obstetric complications was compared between maternal exposure and non-exposure. ^γBecause the prevalence of SLE was largely higher in female, (female: male = 14:1 in Taiwan, 2011) we only calculated the odds ratio of maternal SLE rather than taken the few male patients into consideration.

Subgroup Analysis Of Ad Patients Stratified By Sex

Table 3 demonstrated the difference of risky diseases between subgroups stratified by sex. The odds ratio of parental RA in boys was 3.070(1.532–6.154) in comparison of 1.448(0.613–3.421) in girls. Parental psoriasis in girls showed the aOR of 1.945(1.129–3.350) which was higher than 1.341(0.772–2.327) in boys.

Table 3

Odds ratios of parental diseases for their children with AD stratified by sex
	The parental diseases existed in
Parental diseases	Neither	Only maternal	Only paternal	Both
Obstetric complications
Preeclampsia
In boys	Ref	1.010(0.975–1.045)
In girls	Ref	0.993(0.958–1.029)
GDM
In boys	Ref	1.159(1.135–1.184)
In girls	Ref	0.993(0.958–1.029)
CI
In boys	Ref	1.112(0.970–1.275)
In girls	Ref	1.237(1.071–1.429)
Autoimmune diseases
RA
In boys	Ref	1.240(1.126–1.364)	1.170(1.047–1.309)	3.070(1.532–6.154)
In girls	Ref	1.182(1.068–1.309)	1.133(1.004–1.280)	1.448(0.613–3.421)
SLE
In boys	Ref	1.237(1.117–1.369)	1.204(0.934–1.552)	1.378(0.252–7.529)
In girls	Ref	1.116(1.002–1.242)	1.321(0.989–1.764)
SS
In boys	Ref	1.166(1.097–1.239)	1.097(0.998–1.206)	1.147(0.894–1.472)
In girls	Ref	1.197(1.124–1.275)	1.159(1.052–1.277)	1.131(0.862–1.484)
AS
In boys	Ref	1.305(1.154–1.475)	1.188(1.110–1.271)	1.262(0.544–2.926)
In girls	Ref	1.293(1.137–1.470)	1.186(1.103–1.275)	1.049(0.437–2.517)
Psoriasis
In boys	Ref	1.200(1.095–1.315)	1.100(1.014–1.194)	1.341(0.772–2.327)
In girls	Ref	1.290(1.174–1.416)	1.138(1.046–1.239)	1.945(1.129–3.350)
Systemic diseases
Anemia
In boys	Ref	1.033(1.016–1.051)	1.041(0.998–1.086)	1.068(1.016–1.123)
In girls	Ref	1.027(1.009–1.045)	1.042(0.997–1.089)	1.114(1.057–1.173)
HTN
In boys	Ref	1.084(1.035–1.135)	1.107(1.075–1.140)	1.321(1.135–1.536)
In girls	Ref	1.046(0.996–1.098)	1.124(1.090–1.158)	1.193(1.018–1.398)
DM
In boys	Ref	1.119(1.084–1.155)	1.093(1.046–1.143)	1.401(1.199–1.637)
In girls	Ref	1.089(1.052–1.127)	1.140(1.090–1.193)	1.317(1.124–1.544)
COPD
In boys	Ref	1.153(1.104–1.204)	1.179(1.136–1.223)	1.224(1.083–1.384)
In girls	Ref	1.224(1.170–1.280)	1.159(1.114–1.206)	1.200(1.056–1.364)
Hyperthyrodism
In boys	Ref	1.190(1.150–1.231)	1.128(1.051–1.210)	0.899(0.636–1.269)
In girls	Ref	1.185(1.142–1.228)	1.169(1.088–1.256)	1.431(1.067–1.920)
OSA
In boys	Ref	1.219(1.063–1.398)	1.195(1.122–1.273)	0.985(0.532–1.824)
In girls	Ref	1.320(1.140–1.528)	1.221(1.145–1.304)	0.362(0.129–1.014)
Allergic diseases
Asthma
In boys	Ref	1.273(1.234–1.313)	1.241(1.200-1.283)	1.520(1.389–1.663)
In girls	Ref	1.301(1.260–1.343)	1.178(1.137–1.221)	1.466(1.335–1.610)
AD
In boys	Ref	1.471(1.443–1.499)	1.330(1.275–1.386)	2.117(1.953–2.295)
In girls	Ref	1.478(1.448–1.509)	1.326(1.269–1.385)	2.020(1.852–2.204)

The present study explored the association between parental autoimmune diseases and AD in their children. Our novel findings illustrated two main points. Firstly, parental AD, asthma, RA and psoriasis increased the risk of AD development in children before 5 years old. Furthermore, the subgroup analysis presented different odds ratios of parental diseases between the sexes of children. Parental RA was more prevalent in male children with AD, while parental psoriasis was more prevalent in female children with AD.

The pathophysiologic mechanism of maternal diseases may be explained by the exposure of IgE autoantibodies during pregnancy. One Swedish study mentioned that higher prevalence of asthma was noted in children born to mothers with SLE during pregnancy.⁴ Another study found that maternal dermatologic and digestive autoimmune diseases were closely associated with subsequent AD in their offspring.⁶ Though the mechanism of relationship between AD and autoimmune diseases remains unclear, it is found that 65% of the patients with SLE had higher level of IgE autoantibodies ¹³, which was also prevalent in 50–60% of patients with RA.¹⁴ Studies suggested that elevation of IgE level and self-reactive T cell during pregnancy could induce autoreactivity in early infancy and subsequently increase the risk of developing AD. ^{15 16}

Additionally, our study also found that both maternal and paternal allergic diseases could be the risk factors, which implied that genes effect also played an important role in AD. Filaggrin is a fundamental protein of skin barrier, and mutation of filaggrin (gene R501X and 2282del4) could be perceived as one of strongest predictors for AD.¹⁷ In other GWAS(genome-wide association studies), filaggrin was not only listed as a characterized risk locus of AD, but its effect on genomic printing was prove to be equal between maternal and paternal alleles.¹⁸ However, filaggrin mutations were more frequent in women,¹⁸ which would lead to closer relationship between maternal atopic diseases and children AD. The adjusted odds ratios (p value) of paternal diseases exposure that compared with maternal disease exposure (as reference group) were showed in Supplemental Table 3 (boys) and Supplemental Table 4 (girls). When compared with maternal AD exposure, the adjusted odds ratio of paternal AD exposure is 0.903 (p < 0.0001) and 0.898 (p < 0.0001) for childhood AD in boys and girls, respectively. Our result showed significant difference and was consistent with the hypothesis.

The distinguishing feature of our study is the subgroup analysis of children’s sexes, which showed the different risk factors for boys and girls, respectively. Studies have presented that early-onset AD was more prevalent in boys, while more females would develop AD after puberty. ¹⁹ Though there are many possible mechanisms, sex hormones may explain the difference of onset and progression between sexes. Studies have mentioned that level of dehydroepiandrosterone (DHEA), precursor of testosterone, was lower in boys because it was controlled by an X-linked gene. Moreover, in the study by Zhang et al, the AD-driven cytokines such as interleukins 4 and 11 were found to promote the expression of enzyme for DHEA. This would increase androgen synthesis in sebocytes and decrease total amounts of triglyceride, which could lead to disruption of epidermal permeability barrier.^{20 21} Adversely, higher level of estrogen was perceived as a protective factor for AD because of its function of reconstitution in skin barrier. Though our study mainly focused on AD development before 5 years old, it is also noted that increased estrogen and progesterone levels after puberty stimulated the activity of Th2 cells, which could lead to exacerbation of AD during premenstrual phase and pregnancy, and impact the development of immune system of the fetus.^{15 21}

Lastly, both RA and psoriasis were found to be associated with AD in several studies. RA and AD shared a similar immune mechanism, including the increased activity of Th17 cells and dysfunction of regulatory T cells.²² While most of the studies considered AD as a Th2-predominating disease in acute phase, the switch to Th1 was noted during the chronic period, which was also found in AD patient who developed RA.^{23 24} On the other hand, although several studies have identified the common susceptibility loci of AD and psoriasis, the coexistance of these diseases still remained controversial because of their difference in immune pathway.^{10 25}As a result, studies suggested that subtypes of AD should also be taken into consideration because there are difference in prominent cytokines among these subtypes.²⁶

The study has a number of strengths. The link between perinatal data in the National Birth Registry and NHIRD enabled us to obtain a real-world data across generation. The participants were drawn from a population-based and highly representative computerized database of medical records. This allowed us to perform our analysis with a real-life setting in an unselected patient population. We took advantage of the detailed medical record in NHIRD and used the strict definitions at least three outpatient visits or one hospital admission with ICD-9 691.²⁷ Additionally, we took a variety of autoimmune diseases into consideration and divided the confounding factors into paternal, maternal and parental(both) influences to compare the effects between parents. Lastly, the subgroup analysis showed different risk factors for AD in boys and girls.

Some limitations should be taken into consideration in this study. First, though the AD patients with ICD-9 code was physician-diagnosed, the lack of confirmation of skin test or sIgE assay still could result in misclassification bias. Hence, we added “at least three outpatient visits or one hospital admission” to the definition of being diagnosed with AD. Second, autoimmune diseases are usually companied with long-term use of immunosuppressive drugs such as corticosteroid, hydroxychloroquine and TNFi (tumor necrosis factor inhibitor). Perinatal exposures to them may give rise to the change in maternal immune system ^{28 29}, and their effects on subsequent AD development in patients’ offspring should be well discussed in further studies. Lastly, data on parental smoking history and socioeconomic status was not recorded in the NHIRD, despite the fact that these parental exposures could be important risk factors for childhood atopic diseases.³⁰ Consequently, we replaced smoking history as chronic obstructive pulmonary disease and listed it as one of the confounding factors.

In conclusion, this 14-year case-control study demonstrated that both paternal and maternal autoimmune diseases are risk factors for atopic dermatitis in their children, especially seen with parental RA and psoriasis. There are also different risk factors between sexes: parental RA for boys and parental psoriasis for girls. Therefore, further studies are needed to investigate the underlying mechanisms in genes and immunology. It is recommended that both obstetricians and pediatricians be aware of the risk of developing childhood AD in children to the patients with autoimmune diseases and support the pregnant patients with adequate medical treatment.

Contributors

Writing (original draft preparation): Y-H H, H-Y L, C-D W, M-S Y

Acquisition of data: J-YH

Writing (review and editing) and analysis and interpretation of data: Y-M H and C-C W

English edition: Paul Yung-Pou Wang

Ethics approval

This study was approved by Chung Shan Medical University Hospital (IRB, CS19009).

Competing Interests

None

Acknowledgements

The study was supported by Chung Shan Medical University Hospital (grant number CSH-2019- C -004)

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Association between parental autoimmune disease and childhood atopic dermatitis varied by sex: a nationwide case–control study

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Abstract

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Introduction

Materials And Methods

Data source

Study Population

Parental Exposures And Baseline Characteristics

Statistical analysis

Results

Demographic Characteristic And Percentage Of Comorbidities

Comparison Of Adjusted Odds Ratios Of Parental Diseases Between Ad Group And Control Group

Subgroup Analysis Of Ad Patients Stratified By Sex

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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Version 1