Birth outcomes of infants born to mothers with alopecia areata: A nationwide population-based study in Korea

doi:10.21203/rs.3.rs-4702480/v1

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Birth outcomes of infants born to mothers with alopecia areata: A nationwide population-based study in Korea

https://doi.org/10.21203/rs.3.rs-4702480/v1

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Data on pregnancy outcomes in patients with alopecia areata (AA) are limited. The aim of this study is to determine the association between maternal AA and risk of adverse birth outcomes in children, we conducted a retrospective cohort study on 45,328 children born to mothers with AA and 4,703,253 controls born to mothers without AA using the Korean National Health Insurance Claims database from 2002 to 2016. Multivariate logistic regression analyses were performed to evaluate the association between maternal AA and the birth outcomes of their children. Infants born to mothers with AA exhibited a significantly higher risk for preterm birth (odds ratio [OR], 1.39; adjusted OR [aOR], 1.14), low birth weight (OR, 1.36; aOR, 1.15), and cesarean section birth (OR, 1.24; aOR, 1.10)than controls. In addition, the risk of congenital malformations was also significantly higher in infants born to mothers with AA (OR, 1.19; aOR, 1.12), especially for malformations of the urinary (OR, 1.33; aOR, 1.18), circulatory (OR, 1.28; aOR, 1.11), nervous (OR, 1.26; aOR, 1.15), and musculoskeletal (OR, 1.19; aOR, 1.13) systems, than controls. Maternal AA is associated with an increased risk of adverse birth outcomes in infants.

Health sciences/Medical research

Health sciences/Medical research/Epidemiology

Health sciences/Medical research/Paediatric research

alopecia areata

birth outcome

pregnancy

preterm birth

low birth weight

congenital malformations

Alopecia areata (AA) is a common polygenic, T cell-mediated autoimmune disorder presenting with non-scarring hair loss.¹ AA is known to be associated with other autoimmune diseases or immune-related inflammatory conditions, including thyroiditis, vitiligo, psoriasis, and systemic lupus erythematosus (SLE).^2–4 Although the collapse of local immune privilege of the hair bulb is thought to be the main pathogenic mechanism of AA, some evidence has shown elevation of inflammatory cytokines or markers in the peripheral blood of patients with AA, indicating that systemic inflammation might be associated with AA development and progression.^5–7

Systemic autoimmune or inflammatory diseases have been demonstrated to affect affect the course of pregnancy and trigger birth complications in offspring. For example, SLE, autoimmune thyroid disease, and inflammatory bowel diseases increase the risk of preterm birth, low birth weight (LBW), cesarean section, congenital heart disease, or congenital malformations.^8–14 However, despite the possible role of systemic inflammation in AA and the highest incidence of AA in women aged 20–40 years, no studies have investigated the neonatal outcomes in maternal AA.

Our study aimed to determine the association between maternal AA and birth outcomes of offspring, including preterm delivery, LBW, delivery by cesarean section, and congenital malformations, using the Korean National Health Insurance (NHI) claims database.

Data sources

This study used the Korean NHI database linked to the National Health Screening Program for Infants and Children (NHSIC) database. The NHI is a government-operated service that provides mandatory insurance to South Korea’s entire population of more than 50 million people. It includes inpatient and outpatient healthcare utilization data, which each medical facility must submit for reimbursement purposes according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.

The NHSIC database records screening data on the growth and development of all the children in Korea. All children are eligible to participate in the NHSIC program up to a maximum of seven times from the age of 4–71 months. At every visit, a physician assesses the children’s overall conditions, including height, weight, nutritional status, and visual acuity, and the results are submitted to the NHI Service. The questionnaire used for history taking in this program includes questions regarding children’s gestational age, mode of delivery, weight at birth, and nutritional habits, such as breastfeeding. Currently, the program covers 80% of children in Korea.

Employed or self-employed individuals become NHI beneficiaries by paying a certain percentage of their income, and their family members become dependents. The children of beneficiaries enroll in the NHI program as dependents immediately after the registration of their birth. Using familial relationship information from the NHI data, we created a nationwide mother–child database. This database includes disease history based on ICD-10 codes of mothers during pregnancy, NHSIC screening data, and disease history based on ICD-10 codes of infants during the first year of life.

This study was approved by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (IRB No. B-1811-507-005). Informed consent to participate was waived by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (IRB No. B-1811-507-005). The study have been performed in accordance with the Declaration of Helsinki.

Study population

The study population consisted of all live singleton infants born between January 1, 2002, and December 31, 2016, and who had matching information with their mothers (n = 4,804,806).

Mothers with AA were defined as those who had three or more documented physician visits per year with diagnostic codes for AA, alopecia totalis, alopecia universalis, or ophiasis (ICD-10 code L63.9, L63.0, L63.1, or L63.2, respectively). The diagnosis was validated using previously described methodology, with a sensitivity of 90.6% and a specificity of 90.8%.³² If the diagnostic code for AA began to be used before the date of delivery, it was defined as a case diagnosed with AA before delivery. When the diagnostic code for AA was used for the first time after delivery, it was considered a case of AA after delivery. If the diagnostic code for AA was not used during the study period, it was considered a case that was unexposed to AA.

Among the 4,804,806 infants, 45,328 and 56,225 were born to mothers diagnosed with AA before and after delivery, respectively. We excluded those born to women diagnosed with AA after delivery to investigate the association between in utero exposure to AA and birth outcomes. The remaining 4,703,253 infants were born to mothers without AA and were defined as the control group.

Assessment of morbidities of mothers during pregnancy

The morbidities of mothers during pregnancy that could affect birth outcomes were assessed based on the currently available scientific literatures^33–37 and determined using ICD-20 codes. These include hypertension (O10.X, O13, O16) and diabetes mellitus (DM) (O24.X), comprising both pre-existing and complicated pregnancy cases and pregnancy-induced cases, and pre-eclampsia (O11.X, O14.X), eclampsia (O15.X), and genitourinary infections during pregnancy (O23.X). Morbidities were defined as mothers having three or more documented visits in outpatient physician contacts or one or more documented hospitalizations with a principal diagnostic code from the codes mentioned above.

Study outcomes

The main outcomes of interest in this study were the birth outcomes of the children, including preterm birth, LBW, cesarean section birth, and congenital malformations. Children were followed up from the time of birth until the age of 1 year for the ICD diagnostic codes and for the NHSIC, which includes the first two checkups. Using the NHSIC questionnaire, preterm birth was defined as a gestational age < 37 weeks, and LBW was defined as a birth weight < 2500 g. For cases that did not complete the NHSIC questionnaire during the follow-up period, preterm (P07.2, P7) and LBW (P7.0, P7.1) were determined by referring to ICD-10 codes. Cesarean section birth was determined using the procedure code of the mother (ICD-10 code O82). Congenital malformations were determined using the diagnostic code of children (ICD-10 codes Q00–Q99). These were further classified according to the affected system and several specific diseases (Supplementary Table 1).

Statistical analysis

The characteristics of mothers with and without AA were compared using Student’s T-test for continuous variables and standardized difference for categorical variables. We used multivariate logistic regression analyses to investigate the association between maternal AA and birth outcomes in their children. The dependent variables were birth outcomes of infants, including preterm birth, LBW, cesarean section birth, and congenital malformations. Potential confounders for adjustment were the age and morbidity during the mothers’ pregnancy. Crude odds ratios (ORs), adjusted ORs (aORs), and 95% confidence intervals (CIs) were reported. All statistical analyses were performed using the STATA statistical package version 15.0 (StataCorp).

Characteristics of infants and mothers

Table 1 shows the characteristics of the infants and their mothers, including maternal morbidity during pregnancy. The mean ages of the mothers were 31.76 and 30.98 years in infants born to mothers with and without AA, respectively. DM (6.53% in mothers with AA vs. 5.03% in mothers without AA) and genitourinary infection (5.53% vs. 4.51%, respectively) showed a tendency to be worse in mothers with AA than in those without AA, although the differences were not sufficiently large to be clinically significant (all standardized differences < 0.1). Other morbidities, such as hypertension during pregnancy, pre-eclampsia, and eclampsia, showed little difference between mothers with and without AA.

Table 1

Characteristics of infants born to mothers with and without AA
Characteristics	Children born to mothers with AA (n = 45,328)	Children born to mothers without AA (n = 4,703,253)	SMD
Sex, no. (%)			0.00179
Male	23,343 (51.50)	2,426,295 (51.59)
Female	21,985 (48.50)	2,276,958 (48.41)
Age of mothers, mean yr ± SD	31.76 ± 3.82	30.98 ± 3.97	–0.20066
Morbidity of mothers during pregnancy, no. (%)
Hypertension	579 (1.28)	54,474 (1.16)	0.01086
Pre-eclampsia	459 (1.01)	51,228 (1.09)	0.00751
Eclampsia	34 (0.08)	5,233 (0.11)	0.01189
Diabetes mellitus	2,961 (6.53)	236,405 (5.03)	0.06457
Genitourinary infection	2,508 (5.53)	211,929 (4.51)	0.04705
AA, alopecia areata; SMD, standardized mean difference

Prenatal outcomes

Among the 45,328 infants born to mothers with AA, 2,223 (4.94%) were defined as preterm birth (1,256/23,343 in male, 967/21,985 in female), and 2,424 (5.35%) were defined as LBW (1,177/23,343 in male, 1,247/21,985 in female) (Table 2). However, 168,325 out of the 4,703,253 (3.58%) controls were defined as preterm birth, and 187,194 out of the 4,703,253 (3.98%) controls were defined as LBW (Table 2). The incidence rates of preterm birth and LBW were significantly higher in infants born to mothers with AA than in controls (OR, 1.39; 95% CI, 1.33–1.45 and OR, 1.36; 95% CI, 1.31–1.42, respectively). After adjusting for maternal age and morbidity during pregnancy, the risks of preterm birth and LBW were attenuated but still higher in infants born to mothers with AA than in controls (aOR, 1.14; 95% CI, 1.10–1.20, and aOR, 1.15; 95% CI, 1.11–1.20, respectively). The cesarean section birth rate was also significantly higher in infants born to mothers with AA before and after adjustment than in controls (OR, 1.24; 95% CI, 1.31–1.42 and aOR, 1.095; 95% CI, 1.08–1.120, respectively) (Table 2).

Table 2

Birth outcomes of children of mothers with AA compared with those of children of mothers without AA
	Incidence		Unadjusted OR (95% CI)	Adjusted OR (95% CI)
	Children born to mothers with AA (n = 45,328)	Children born to mothers without AA (n = 4,703,253)
Preterm birth (< 37 wk)	4.90% (2,223/45,328)	3.58% (168,325/4,703,253)	1.39 (1.33–1.45)	1.149 (1.10–1.20)
Low birth weight (< 2500 g)	5.35% (2,424/45,328)	3.98% (187,194/4,703,253)	1.36 (1.301–1.42)	1.15 (1.11–1.20)
Cesarean section birth	41.04% (18,601/45,328)	35.99% (1,692,727/4,703,253)	1.24 (1.22–1.26)	1.095 (1.08–1.12)
Congenital malformation	11.28% (5,112/45,328)	9.68% (455,352/4,703,253)	1.19 (1.15–1.22)	1.12 (1.09–1.16)
AA, alopecia areata; OR, odds ratio; 95% CI, 95% confidence interval

Congenital malformations

Among infants born to mothers with AA, 11.28% (5,112/45,328) were diagnosed with congenital malformations, whereas 9.68% (455,325/4,703,253) were so in controls (Table 2). The incidence rate of congenital malformation was significantly higher in infants born to mothers with AA than in controls (OR, 1.19; 95% CI, 1.15–1.22), and the risk was still higher after adjustment (aOR, 1.12; 95% CI, 1.09–1.16). Table 3 shows the incidence of congenital malformation according to systematic classification, including several specific diseases, in both groups. Specifically, the risks of congenital malformation of the urinary system, including cystic kidney disease (337/45,328 in infants born to mothers with AA vs. 26,417/4,703,253 in controls; OR, 1.33; 95% CI, 1.10–1.48; aOR, 1.18; 95% CI, 1.06–1.32); malformation of the circulatory system, including cardiac septal defect (1,340/45,328 vs. 109,478/4,703,253; OR, 1.28; 95% CI, 1.21–1.35; aOR, 1.113; 95% CI, 1.05–1.18); malformation of the nervous system, including spina bifida (153/45,328 vs. 12,636/4,703,253; OR, 1.26; 95% CI, 1.07–1.48; aOR, 1.15; 95% CI, 0.98–1.35); and malformation of the musculoskeletal system, including polydactyly (1,025/45,328 vs. 89,503/4,703,253; OR, 1.19; 95% CI, 1.12–1.27; aOR, 1.13; 95% CI, 1.06–1.21) were higher in infants from mothers with AA than in controls.

Table 3

Systematic congenital malformations based on the presence or absence of AA in mothers
	Incidence		Unadjusted OR (95% CI)	Adjusted OR (95% CI)
	Children born to mothers with AA (n = 45,328)	Children born to mothers without AA (n = 4,703,253)
Congenital malformations of the nervous system	0.39%(153/45,328)	0.27% (12,636/4,703,253)	1.26 (1.07–1.48)	1.15 (0.98–1.35)
Spina bifida	0.11% (48/45,328)	0.10% (4,493/4,703,253)	1.11 (0.834–1.474)	0.94 (0.71–1.25)
Congenital malformations of the eye, ear, face, and neck	1.82% (823/45,328)	1.67% (78,644/4,703,253)	1.09 (1.02–1.17)	1.14 (1.06–1.22)
Cleft lip and cleft palate	0.07% (31/45,328)	0.07% (3,275/4,703,253)	0.98 (0.69–1.40)	0.96 (0.67–1.36)
Congenital malformations of the circulatory system	2.96% (1,340/45,328)	2.33% (109,478/4,703,253)	1.28 (1.21–1.35)	1.11 (1.05–1.18)
Congenital malformations of the cardiac septa	2.80% (1,268/45,328)	2.13% (100,292/4,703,253)	1.32 (1.25–1.40)	1.111 (1.05–1.18)
Congenital malformations of the respiratory system	0.18% (82/45,328)	0.20% (9,342/4,703,253)	0.91 (0.73–1.13)	0.99 (0.80–1.23)
Congenital malformations of the Digestive system	2.70% (1,222/45,328)	2.37% (111,695/4,703,253)	1.14 (1.08–1.21)	1.09 (1.03–1.15)
Congenital absence, atresia, and stenosis of the large intestine	0.06% (26/45,328)	0.05% (2,334/4,703,253)	1.16 (0.79–1.7029)	1.07 (0.73–1.58)
Congenital malformations of the genital organs	1.04% (469/45,328)	0.86% (40,438/4,703,253)	1.21 (1.10–1.32)	1.12 (1.02–1.23)
Undescended testicles	0.92% (415/45,328)	0.80% (37,541/4,703,253)	1.15 (1.04–1.27)	1.07 (0.97–1.18)
Hypospadias	0.10% (45/45,328)	0.80% (4,387/4,703,253)	1.06 (0.79–1.43)	1.02 (0.756–1.37)
Congenital malformations of the urinary system	0.74% (337/45,328)	0.56% (26,419/4,703,253)	1.33 (1.19–1.48)	1.18 (1.06–1.32)
Cystic kidney disease	0.07% (30/45,328)	0.07% (3,387/4,703,253)	0.912 (0.64–1.32)	0.88 (0.62–1.27)
Congenital malformations of the musculoskeletal system	2.26% (1,025/45,328)	1.90% (89,503/4,703,253)	1.19 (1.12–1.27)	1.13 (1.07–1.21)
Polydactyly	0.21% (96/45,328)	0.19% (9,023/4,703,253)	1.10 (0.90–1.35)	1.14 (0.93–1.40)
Other congenital malformations	0.53% (239/45,328)	0.48% (22,679/4,703,253)	1.09 (0.96–1.24)	1.10(0.97–1.25)
Chromosomal abnormalities, NEC	0.13% (61/45,328)	0.15% (6,955/4,703,253)	0.91 (0.707–1.171)	0.91 (0.705–1.169)
AA, alopecia areata; OR, odds ratio; 95% CI, 95% confidence interval; NEC, not elsewhere classified

In this nationwide study, we observed that infants born to mothers with AA had an increased risk of preterm birth, LBW, and cesarean section birth. Furthermore, maternal AA was associated with an increased risk of congenital malformations, including those of the urinary, circulatory, nervous, and musculoskeletal systems. To the best of our knowledge, this is the first study to investigate the birth outcomes of offspring of mothers with AA.

Although active studies have been conducted on the effect of maternal systemic autoimmune or autoinflammatory diseases on the birth outcomes of their offspring^14–16, there is little information regarding autoimmune or autoinflammatory skin diseases, and most of them are limited to psoriasis. A Taiwanese record-linkage study demonstrated an increased risk of LBW in infants from mothers with severe psoriasis¹⁷, and a Swedish population-based study demonstrated that infants with maternal psoriasis had an increased risk of congenital malformation¹⁸. Jo et al. recently reported that maternal AA increased the risk of abortion and ectopic pregnancy. Nevertheless, the results of this study focused only on maternal outcomes and not on the outcomes of offspring. The present study used big data based on the NHI and created a unique mother–child database using familial relationship information. In this way, we obtained a large sample size, allowing us to have sufficient statistical power to analyze birth outcomes, including specific congenital malformations by the affected system.

Although the ORs of birth complications were not dramatically higher in infants from AA mothers, our results are expected to have certain clinical significance considering that AA is a common autoimmune disease, with a lifetime risk of approximately 2% that frequently affects women of childbearing ages. We believe our data provide evidence for the necessity of preconception counseling, active surveillance during pregnancy, and thorough neonatal care of offspring in pregnant women with AA. Meanwhile, in our results, mothers with AA showed a tendency to have worse maternal obstetric outcomes compared with mothers without AA, particularly for gestational DM and genitourinary infection. Considering that the strengths of association for birth outcome of the study group were attenuated after adjusting for these comorbid maternal obstetric conditions, close monitoring and thorough management of pregnancy morbidity of mothers with AA might improve the outcomes of their children.

The exact mechanism underlying the worse outcomes in infants from AA mothers is unclear. Previous studies have shown significantly higher T helper 1 (Th 1) and Th 17 cytokines and lower regulatory T-cell cytokine levels not only in the lesional skin of patients with AA but also in the peripheral blood^19,20. Excessive immunity of effector T cells causes pathological inflammation at the maternal–fetal interface and may lead to preterm labor and birth, spontaneous abortion, intrauterine growth retardation, and pre-eclampsia.^21–24 On the other hand, regulatory T cells regulate maternal alloreactive T cells and induce feto-maternal immune tolerance, which may reduce perinatal complications caused by effector T cells.²⁵ And inadequate number or functional deficiency of regulatory T cells is associated with spontaneous abortion and pre-eclampsia.²⁶ Taken together, abnormal regulation of particular T-cell cytokines in mothers with AA might be an important pathogenetic mechanism that causes worse birth outcomes of their children in our study.

Regarding congenital malformations, in utero exposure to AA medications may be considered a main factor. Unfortunately, medication history during pregnancy was not evaluated in this study. However, the effects of drugs are expected to be small as AA is not a life-threatening condition, and most patients do not take medications for AA during their pregnancy in Korea. In addition, the medications used in patients with severe AA, including corticosteroids and cyclosporine, have generally failed to cause adverse outcomes related to pregnancy in humans.^27–31 Further investigations are necessary to elucidate the mechanism of higher teratogenicity in pregnancy of maternal AA.

Our study has some limitations. First, the NHI claims database may include misdiagnoses that can lead to misclassification bias. To reduce such errors, we defined patients with AA according to a previously validated algorithm.³² Second, we were unable to evaluate some factors associated with the outcomes, including medication, body mass index before pregnancy, and history of smoking and alcohol consumption which might influence pregnancy outcomes. Third, the NHI claims database did not provide detailed clinical information on individual patients, including disease onset, duration, severity, and activity or treatment histories. Finally, some congenital anomalies that are sometimes not identified early in life may not be included. However, we considered the risk significantly low to affect the results.

In conclusion, Infants born to mothers with AA had a significantly increased risk of birth comorbidities. Further investigation is required to clarify the causal association between maternal AA and these comorbidities in offspring. Preterm birth, LBW, and congenital anomalies are major factors contributing to neonatal mortality and morbidity. Considering that AA is a common skin disease that can occur in women of childbearing age, our results may provide evidence of the appropriateness of close perinatal monitoring and consultation in pregnancy for maternal AA.

AA alopecia areata

aOR adjusted odds ratio

CIs confidence intervals

DM diabetes mellitus

ICD-10 International Statistical Classification of Diseases and Related Health Problems, Tenth Revision

LBW low birth weight

IRB Institutional Review Board

NHI National Health Insurance

OR odds ratio

Th T helper

Conflict of Interest: None declared.

Funding sources:

This study was supported by the Seoul National University Bundang Hospital Research Fund (grant no. 02-2020-0037).

Author Contribution

Jung-Won Shin contributed conceptualization devised methods and drafted an article.Taeuk Kang, Heather Swan contributed validationKyungho Paik, Chang-Hun Huh contributed investigation.Hyun Jung Kim supervised the project and devised methods.All authors reviewed and revised article.

Acknowledgement

This study was supported by the Seoul National University Bundang Hospital Research Fund (grant no. 02-2020-0037).

Data Availability

Data subject to third party restrictions. This study used the Korean NHI database linked to the National Health Screening Program for Infants and Children (NHSIC) database. The NHI is a government-operated service that provides mandatory insurance to South Korea’s entire population. According to data use agreement between NHI and research team, NHI does not allow sharing of data with third party due to privacy issue. If you want to receive original data, you must contract with the National Health Insurance in Korea and directly request the data.

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Birth outcomes of infants born to mothers with alopecia areata: A nationwide population-based study in Korea

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Abstract

Introduction

Methods

Data sources

Study population

Assessment of morbidities of mothers during pregnancy

Study outcomes

Statistical analysis

Results

Characteristics of infants and mothers

Prenatal outcomes

Congenital malformations

Discussion

Abbreviations

Declarations

Funding sources:

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Supplementary Files

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