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. 2021 Mar 22;16(3):e0248651. doi: 10.1371/journal.pone.0248651

Pregnancy outcomes in women with vitiligo: A Taiwanese nationwide cohort study

Chih-Tsung Hung 1,2, Hsin-Hui Huang 3, Chun-Kai Wang 4, Chi-Hsiang Chung 5,6, Chang-Huei Tsao 7,8, Wu-Chien Chien 5,7,9,*, Wei-Ming Wang 1,2,*
Editor: Christy Pu10
PMCID: PMC7984608  PMID: 33750961

Abstract

Vitiligo is perceived as an autoimmune skin disease. Previous studies showed conflicting data about vitiligo and pregnancy outcomes. To delineate the associations between vitiligo and the pregnancy outcomes, we used the National Health Insurance Research Database of Taiwan to conduct a retrospective cohort study from January 1, 2000 to December 31, 2015. This study population was composed of 1,096 women with vitiligo and 4,384 women without vitiligo, who were all matched according to age, comorbidity, and index year. Compared with the non-vitiligo controls, women with vitiligo had a higher risk of abortion (aHR 1.158, 95% confidence interval (CI) 1.095–1.258, P < .001). Perinatal events, such as preterm delivery, pre-eclampsia/eclampsia, gestational diabetes mellitus, stillbirth, and intrauterine growth retardation, were not different between both groups (aHR 1.065, 95% CI 0.817–1.157, P = .413). To determine if systemic treatment before conception decreases the risk of abortion, we assessed the medical history of pregnant women with vitiligo 1 year before pregnancy. Patients who were treated with oral medications had a lower risk of abortion than those who were not (aHR: 0.675, 95% CI: 0.482–0.809, P < .001). Our study indicates that there is a higher risk of abortion in pregnant women with vitiligo and the control of disease activity with systemic treatment before conception could improve pregnancy outcomes.

Introduction

Vitiligo is an acquired skin disease with progressive dermal and mucosal depigmentation. In this condition, CD8+ cytotoxic T cells destruct the epidermal melanocytes [1, 2]. Depending on the different studied populations, its prevalence varies from 0.064% to 1% [3, 4]. Patients with vitiligo may feel stigmatized, have poor body image, have low self-esteem, and experience extreme psychological distress [5, 6]. A recent meta-analysis study revealed that one in four people with vitiligo suffers from depression [7].

Vitiligo is not only a cosmetic problem but also a chronic autoimmune disease. Several systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis (RA), and autoimmune thyroiditis (e.g., Hashimoto thyroiditis and Graves’ disease) are associated with vitiligo [3, 8]. Autoimmune diseases are also associated with obstetric complications [9, 10]. However, the association between vitiligo and pregnancy outcomes remains unclear [11, 12]. Therefore, this study aimed to delineate the association between vitiligo and pregnancy outcomes such as abortion, preterm delivery, pre-eclampsia/eclampsia, gestational diabetes mellitus (DM), stillbirths, intrauterine growth retardation (IUGR) by using Taiwan National Health Insurance Research Database.

Material and methods

Ethics statement

Our study conformed to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Tri-Service General Hospital (TSGHIRB C202005017). Considering that the Taiwan National Health Insurance Research Database (NHIRD) contains fully anonymized linked information, which does not affect the welfare and right of the subjects, the requirement for informed consent from our participants was waived.

Data sources

In Taiwan, >99% of the population has joined the National Health Insurance, which is a mandatory single-payer social insurance. The Taiwan NHIRD contains many anonymized linked data, including outpatient care, inpatient care, emergency care, treatment procedures, and prescription drugs. Physicians diagnosed their patients using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) in the NHIRD between 2000 and 2015. The diagnoses in the NHIRD have been proven accurate by numerous previous studies [13, 14].

Study participants

The selection of the study participants is depicted in Fig 1. We enrolled patients with vitiligo (ICD-9-CM code 709.01) and with data of their first pregnancy (ICD-9-CM code V22-V23) from the Longitudinal Health Insurance Database between January 1, 2000 and December 31, 2015 in Taiwan. We evaluated only the first pregnancy to avoid bias related to multiple outcomes in the same women. Meanwhile, we excluded those who were pregnant or diagnosed with SLE, Sjögren’s syndrome, or RA before 2000, or before the first visit for vitiligo. All patients aged below 20 years were also excluded. The study population was composed of 1,096 women with vitiligo and 4,384 women without vitiligo, who were all matched according to age, comorbidity, and index year.

Fig 1. The flowchart of study population selection.

Fig 1

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This study included 1,096 first and subsequent singleton pregnancies in women with vitiligo and 4,384 pregnancies in women without vitiligo from 2000 to 2015.

Outcome measures

Pregnancy outcomes included live births (ICD-9-CM code 650–655, 656.0–656.3, 656.6–656.9, 669.50–669.51), abortion (ICD-9-CM code 632, 634, 637), cesarean delivery (ICD-9-CM code 669.7), and other perinatal events. Elective abortion (ICD-9-CM code 779.6) was also excluded in both groups. Perinatal events comprised preterm delivery (ICD-9-CM code 644.0–64.2), pre-eclampsia/eclampsia (ICD-9-CM code 642.4–642.7), gestational DM (ICD-9-CM code 648.8), stillbirths (ICD-9-CM code 656.4), and IUGR (ICD-9-CM code 656.5).

Until the end of the study, we assessed the comorbid diseases of women who had experienced abortion. These diseases included SLE (ICD-9-CM code 710.0), Sjögren’s syndrome (ICD-9-CM code 710.2), RA (ICD-9-CM code 714.0), Graves’ disease (ICD-9-CM code 242), Hashimoto thyroiditis (ICD-9-CM code 245.2), psoriasis (ICD-9-CM code 696.1), and atopic dermatitis (ICD-9-CM code 691.8).

Furthermore, we evaluated whether systemic treatment before conception decreases the risk of abortion and assessed the medical history of women with vitiligo 1 year before pregnancy. We determined the prescribed oral medications and phototherapy by using drug and procedure number in the NHIRD.

Covariates

The covariates included the age groups (20–29, 30–39, and 40–49 years), comorbidity, seasons, level of care, geographical area of residence, and urbanization level. To evaluate comorbidities, we used Charlson comorbidity index (CCI), which comprises various comorbidities, including cerebrovascular disease, dementia, hemiplegia, chronic pulmonary disease, congestive heart failure, myocardial infarction, peripheral vascular disease, connective tissue disease, diabetes, renal and liver disease, ulcer disease, any tumor, leukemia, lymphoma, and AIDS; all comorbidity scores in each study group were totaled to obtain the CCI [15]. The higher the score, the more the comorbidity burdens.

Statistical analysis

Categorical variables were compared using the chi-squared test, whereas the continuous variables were evaluated using Fisher’ exact test and t-test. We calculated the incidence rate (per 105 person-months) by dividing the number of women with perinatal events by the total person-months of each group. Adjusted hazard ratios and 95% confidence intervals (CIs) were calculated using the Multivariable Cox proportional hazard model. A two-tailed P value < .001 and a CI not including 1 were considered statistically significant. All statistical data were analyzed using the SPSS software version 22 (SPSS Inc., Chicago, Ill., USA).

Results

This cohort study included 1,096 pregnant women with vitiligo and 4,384 pregnant women without vitiligo who were both recorded in the NHIRD between 2000 and 2015. Both study groups had similar age and comorbidities (Table 1). The peak age group of pregnancy was 20–29 years (52.28%), followed by 30–39 years (46.72%).

Table 1. Maternal characteristics of study population in the baseline.

Vitiligo Total With Without P
Variables N % n % N %
Total 5,480 1,096 20.00 4,384 80.00
Age (years) 29.53±5.31 29.62±5.48 29.51±5.27 0.540
Age groups (years) 0.999
20–29 2,865 52.28 573 52.28 2,292 52.28
30–39 2,560 46.72 512 46.72 2,048 46.72
40–49 55 1.00 11 1.00 44 1.00
CCI 1.04±1.94 1.10±1.85 1.03±1.96 0.285
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P: Chi-squared/Fisher’s exact test on category variables and t-test on continue variables. CCI, Charlson comorbidity index.

After adjusting for age, comorbidity, season, location, urbanization level, and level of care, the women with vitiligo had a lower live-birth rate (aHR: 0.800, 95% CI: 0.727–0.824, P < .001, Table 2) and a higher abortion rate (aHR: 1.158, 95% CI: 1.095–1.258, P < .001) than those without vitiligo. Subgroup analysis of the total perinatal events, including preterm delivery, pre-eclampsia/eclampsia, gestational DM, stillbirths, and IUGR, revealed no significant differences between both groups (aHR: 1.065, 95% CI: 0.817–1.157, P = .413).

Table 2. Risks of maternal and infant outcomes in women with vitiligo compared with those without vitiligo.

Vitiligo With n = 1,096 Without n = 4,384 With vs. Without (Reference)
Pregnancy outcomes Events PMs Rate (per 105 PMs) Events PMs Rate (per 105 PMs) Adjusted HR 95% CI 95% CI P
Live births 634 13,960.70 4,541.32 2,679 55,841.46 4,797.51 0.800 0.727 0.824 <0.001
Abortion 117 13,823.46 846.39 354 55,308.49 640.05 1.158 1.095 1.258 <0.001
Cesarean delivery 260 13,816.85 1,881.76 1,047 55,306.39 1,893.09 0.901 0.797 1.008 0.425
Perinatal events
Total 81 13,923.60 581.75 304 55,643.17 546.34 1.065 0.817 1.157 0.413
Preterm delivery 24 12,963.62 185.13 86 54,333.79 158.28 1.028 0.788 1.168 0.362
Pre-eclampsia / eclampsia 21 13,487.39 155.70 71 54,525.03 130.22 1.157 0.783 1.258 0.264
Gestational DM 14 13,923.56 100.55 58 55,643.17 104.24 1.012 0.715 1.108 0.699
Stillbirths 9 13,892.33 64.78 35 55,538.33 63.02 1.004 0.651 1.091 0.734
IUGR 13 13,894.55 93.56 54 55,587.60 97.14 1.031 0.763 1.334 0.415
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Adjusted HR, Adjusted Hazard ratio: adjusted with age, comorbidity, season, location, urbanization level, and level of care; CI = confidence interval; DM, diabetes mellitus; IUGR, intrauterine growth retardation; PMs = Person-months

To determine if systemic treatment before conception decreases risk of abortion, we assessed the medical history of pregnant women with vitiligo 1 year before the pregnancy; those who received oral medications and/or phototherapy for at least 3 months were included in the systemic treatment group. Patients with vitiligo undergoing systemic treatment (n = 296) were compared with those without systemic treatment (n = 800, Table 3). Patients who were treated with oral medications had a lower risk of abortion than those who were not (aHR: 0.675, 95% CI: 0.482–0.809, P < .001). In the subgroup analysis of patients with oral medications, the risk of abortion was lowest in patients taking oral steroids (aHR: 0.596, 95% CI: 0.463–0.774, P < .001), followed by those taking methotrexate (aHR: 0.720, 95% CI: 0.575–0.873, P < .001). Meanwhile, patients treated with azathioprine demonstrated no significant differences (aHR: 0.837, 95% CI: 0.746–1.238, P = .211). Moreover, seven patients underwent combined oral medications and phototherapy, and no abortion was observed.

Table 3. Systemic treatment before conception reduced risk of abortion in women with vitiligo.

Pregnancy outcomes Vitiligo Population Outcomes PMs Rate (per 105 PMs) Adjusted HR 95% CI 95% CI P
Abortion Total 1,096 117 13,823.46 846.39
Without systemic treatment 800 95 10,446.40 909.40 Reference
Oral medication or Phototherapy 296 22 3,377.06 651.45 0.755 0.710 0.979 0.030
Oral medication only 231 17 2,554.19 665.57 0.675 0.482 0.809 <0.001
oral steroid only 171 12 1,915.51 626.46 0.596 0.463 0.774 <0.001
oral MTX only 36 3 406.18 738.59 0.720 0.575 0.873 <0.001
oral AZA only 24 2 232.50 860.22 0.837 0.746 1.238 0.211
Phototherapy only 58 5 622.09 803.74 0.821 0.738 0.987 0.034
Combined oral medication and phototherapy 7 0 200.78 0.00 0.000 - - 0.975
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Adjusted HR, Adjusted Hazard ratio: adjusted with age, comorbidity, season, location, urbanization level, and level of care; CI = confidence interval; PMs, Person-months; AZA, Azathioprine; MTX, methotrexate.

To identify the incidence of various comorbid diseases, we followed women who experienced abortion until the end of study (Table 4). Patients with vitiligo who experienced abortion had a higher risk of SLE (aHR: 2.146, 95% CI: 1.325–2.897, P < .001), followed by the risks of RA (aHR: 2.068, 95% CI 1.297–2.568, P < .001) and Sjögren’s syndrome (aHR: 1.873, 95% CI: 1.124–2.335, P < .001), than those without vitiligo. Furthermore, Hashimoto thyroiditis was identified in one patient in the vitiligo group, but none in the control group. Meanwhile, psoriasis and atopic dermatitis revealed no significant differences.

Table 4. Rates of various comorbid diseases among women with abortion.

Vitiligo With (n = 117) Without (n = 354) With vs. Without (Reference)
Comorbid diseases Events PYs Rate (per 105 PYs) Events PYs Rate (per 105 PYs) Adjusted HR 95% CI 95% CI P
SLE 4 1,593.16 251.07 6 5,434.06 110.41 2.146 1.325 2.897 <0.001
RA 6 1,541.18 389.31 10 5,306.10 188.46 2.068 1.297 2.568 <0.001
Sjögren’s syndrome 10 1,478.26 676.47 19 5,264.65 360.90 1.873 1.124 2.335 <0.001
Graves’ disease 0 1,611.87 0.00 0 5,574.69 0.00 - - - -
Hashimoto thyroiditis 1 1,612.51 62.02 0 5,547.25 0.00 - - - -
Psoriasis 2 1,584.28 126.24 6 5,462.76 109.83 1.125 0.523 1.735 0.437
Atopic dermatitis 2 1,608.26 124.36 4 5,490.65 72.85 1.402 0.861 2.001 0.288
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Adjusted HR, Adjusted Hazard ratio: adjusted with age, comorbidity, season, location, urbanization level, and level of care; CI = confidence interval; PYs, Person-years; RA, Rheumatoid arthritis; SLE, Systemic lupus erythematosus

Discussion

Currently, data about the association between vitiligo and pregnancy outcomes are inconsistent [11, 12]. In a single-institution, retrospective, and comparative study, the pregnancy outcomes of 79 women with vitiligo and 186,143 controls without vitiligo were not different [11]. In 2018, a large Korean cohort study using the Korean National Health Insurance Claims database from 2007 to 2016 was published [12]. The results of this previous study revealed a significant lower rate of live births (odds ratio: 0.780, P < .001) and a higher rate of spontaneous abortion (odds ratio: 1.250, P < .001) in pregnant women with vitiligo (n = 4,738) than in pregnant age-matched controls without vitiligo (n = 47,380). In addition, a more extensive disease was associated with a higher risk of abortion and a lower live-birth rate than limited disease. In this study, we revealed that pregnant women with vitiligo had a higher risk of abortion, with an aHR of 1.158 (P < .001), and a lower live-birth rate, with an aHR of 0.800 (P < .001).

Vitiligo is a kind of autoimmune disease in which T cells are involved in the pathogenesis [16–18]. In a recent study, the number of circulating Th1 and Th17 were higher in patients with vitiligo than in healthy controls. In active nonsegmental vitiligo, the ratios of Th1/Tregs and Th17/Tregs in circulation are both elevated [19]. The Th1/Th2 balance that switches toward a Th2-dominated cytokine profile during pregnancy might be an important mechanism for maternal immunotolerance of the fetus [20, 21]. However, Th1 immune response may be associated with abortion [22]. A previous study had characterized maternal CD4 T-cell effector subsets during pregnancy (women with normal pregnancy, cross-sectional cohort, n = 71; longitudinal cohort, n = 17; compared with women with recurrent miscarriage, n = 24) by longitudinal analysis of the peripheral blood, and the results revealed that women with recurrent miscarriage had an increased proportion of Th1 and Th17 cells and related cytokines such as IFN-γ and IL-17 [23]. Therefore, immune dysregulation in vitiligo may cause abortion and reduce the rate of live births.

Flares of autoimmune disease activity during pregnancy are unfavorable, increasing the risk of abortion and premature birth [24, 25]. In our study, we sought to understand the impact of systemic treatment on pregnancy outcomes. We found that the patients with vitiligo treated with oral medication before the pregnancy had a decreased risk of abortion. Therefore, disease control with systemic treatment before conception seems to be important, but further investigation is required to prove these findings.

Moreover, patients with vitiligo have higher risks of autoimmune diseases, thyroiditis, alopecia areata, atopic dermatitis, and psoriasis [3, 8, 26–28]. In Taiwan, a large nationwide study presented by Chen et al. revealed that the risks of SLE, Sjögren’s syndrome, and RA were higher in patients with vitiligo aged 60–79 years [3]. In this study, we followed the women (aged 20–49 years) who had experienced abortion until the end of the study to determine the various comorbid diseases. The results showed a higher risk of SLE, followed by RA and Sjögren’s syndrome, in patients with vitiligo who had experienced abortion than in controls without vitiligo. Regarding thyroiditis, one case of Hashimoto thyroiditis was found in the vitiligo group but none in the control group.

As a strength of this study, it has a nationwide retrospective cohort study design utilized for investigating pregnancy outcomes in women with vitiligo in Taiwan. By using NHIRD, we not only could trace back the medical history before pregnancy to determine the impact of systemic treatment on the pregnancy outcomes but also identify the comorbid diseases among women who manifested abortion throughout the study period. However, this study also has some limitations. First, the NHIRD data lack clinical presentations of vitiligo, including body surface area, lesion sites, family history, laboratory parameters, genetics, alcohol use, smoking, and the body mass index. Therefore, we cannot elucidate whether these confounders and the lesion size affect the associations between vitiligo and pregnancy outcomes. Second, the main study population was Taiwanese. Thus, ethnic discrepancy could exist. Third, coding error is possible. To minimize this bias, we defined study patients with vitiligo as those who were diagnosed by dermatologists, and the pregnancy outcomes were coded by obstetricians.

Conclusions

Pregnant women with vitiligo were significantly associated with an increased risk of abortion, and systemic treatment before conception could improve pregnancy outcomes.

Acknowledgments

This study is based in part on data form the National Health Insurance Research Database provided by the Health and Welfare Data Science center, Ministry of Health and Welfare (HWDC, MOHW), and managed by National Health Research Institutes.

Data Availability

All relevant data are within the manuscript.

Funding Statement

This study was supported by grants from Tri-Service Hospital Research Foundation (TSGH-B-109-010, TSGH-D-109-050, and TSGH-E110219). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16: 90–100. 10.1034/j.1600-0749.2003.00023.x [DOI] [PubMed] [Google Scholar]
  • 2.Garbelli S, Mantovani S, Palermo B, Giachino C. Melanocyte-specific, cytotoxic T cell responses in vitiligo: the effective variant of melanoma immunity? Pigment Cell Res. 2005;18: 234–242. 10.1111/j.1600-0749.2005.00244.x [DOI] [PubMed] [Google Scholar]
  • 3.Chen YT, Chen YJ, Hwang CY, Lin MW, Chen TJ, Chen CC, et al. Comorbidity profiles in association with vitiligo: a nationwide population-based study in Taiwan. J Eur Acad Dermatol Venereol. 2015;29: 1362–1369. 10.1111/jdv.12870 [DOI] [PubMed] [Google Scholar]
  • 4.Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE, Vitiligo Working G. New discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol. 2017;77: 1–13. 10.1016/j.jaad.2016.10.048 [DOI] [PubMed] [Google Scholar]
  • 5.Ongenae K, Dierckxsens L, Brochez L, van Geel N, Naeyaert JM. Quality of life and stigmatization profile in a cohort of vitiligo patients and effect of the use of camouflage. Dermatology. 2005;210: 279–85. 10.1159/000084751 [DOI] [PubMed] [Google Scholar]
  • 6.Ongenae K, Van Geel N, De Schepper S, Naeyaert JM. Effect of vitiligo on self-reported health-related quality of life. Br J Dermatol. 2005;152: 1165–1172. 10.1111/j.1365-2133.2005.06456.x [DOI] [PubMed] [Google Scholar]
  • 7.Osinubi O, Grainge MJ, Hong L, Ahmed A, Batchelor JM, Grindlay D, et al. The prevalence of psychological comorbidity in people with vitiligo: a systematic review and meta-analysis. Br J Dermatol. 2018;178: 863–878. 10.1111/bjd.16049 [DOI] [PubMed] [Google Scholar]
  • 8.Lee H, Lee MH, Lee DY, Kang HY, Kim KH, Choi GS, et al. Prevalence of vitiligo and associated comorbidities in Korea. Yonsei Med J. 2015;56: 719–725. 10.3349/ymj.2015.56.3.719 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Gomes V, Mesquita A, Capela C. Autoimmune diseases and pregnancy: analysis of a series of cases. BMC Res Notes. 2015;8: 216. 10.1186/s13104-015-1177-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Kolstad KD, Mayo JA, Chung L, Chaichian Y, Kelly VM, Druzin M, et al. Preterm birth phenotypes in women with autoimmune rheumatic diseases: a population-based cohort study. BJOG. 2020;127: 70–78. 10.1111/1471-0528.15970 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Horev A, Weintraub AY, Sergienko R, Wiznitzer A, Halevy S, Sheiner E. Pregnancy outcome in women with vitiligo. Int J Dermatol. 2011;50: 1083–1085. 10.1111/j.1365-4632.2010.04839.x [DOI] [PubMed] [Google Scholar]
  • 12.Park KY, Kwon HJ, Wie JH, Lee HH, Cho SB, Kim BJ, et al. Pregnancy outcomes in patients with vitiligo: A nationwide population-based cohort study from Korea. J Am Acad Dermatol. 2018;79: 836–842. 10.1016/j.jaad.2018.02.036 [DOI] [PubMed] [Google Scholar]
  • 13.Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute myocardial infarction cases in the national health insurance research database in taiwan. J Epidemiol. 2014;24: 500–507. 10.2188/jea.je20140076 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Cheng CL, Chien HC, Lee CH, Lin SJ, Yang YH. Validity of in-hospital mortality data among patients with acute myocardial infarction or stroke in National Health Insurance Research Database in Taiwan. Int J Cardiol. 2015;201: 96–101. 10.1016/j.ijcard.2015.07.075 [DOI] [PubMed] [Google Scholar]
  • 15.Needham DM, Scales DC, Laupacis A, Pronovost PJ. A systematic review of the Charlson comorbidity index using Canadian administrative databases: a perspective on risk adjustment in critical care research. J Crit Care. 2005;20: 12–19. 10.1016/j.jcrc.2004.09.007 [DOI] [PubMed] [Google Scholar]
  • 16.Wankowicz-Kalinska A, van den Wijngaard RM, Tigges BJ, Westerhof W, Ogg GS, Cerundolo V, et al. Immunopolarization of CD4+ and CD8+ T cells to Type-1-like is associated with melanocyte loss in human vitiligo. Lab Invest. 2003;83: 683–695. 10.1097/01.lab.0000069521.42488.1b [DOI] [PubMed] [Google Scholar]
  • 17.Yang L, Wei Y, Sun Y, Shi W, Yang J, Zhu L, et al. Interferon-gamma inhibits melanogenesis and induces apoptosis in melanocytes: a pivotal role of CD8+ cytotoxic t lymphocytes in vitiligo. Acta Derm Venereol. 2015;95: 664–670. 10.2340/00015555-2080 [DOI] [PubMed] [Google Scholar]
  • 18.Zhang BX, Lin M, Qi XY, Zhang RX, Wei ZD, Zhu J, et al. Characterization of circulating CD8+T cells expressing skin homing and cytotoxic molecules in active non-segmental vitiligo. Eur J Dermatol. 2013;23: 331–338. 10.1684/ejd.2013.2011 [DOI] [PubMed] [Google Scholar]
  • 19.Zhen Y, Yao L, Zhong S, Song Y, Cui Y, Li S. Enhanced Th1 and Th17 responses in peripheral blood in active non-segmental vitiligo. Arch Dermatol Res. 2016;308: 703–710. 10.1007/s00403-016-1690-3 [DOI] [PubMed] [Google Scholar]
  • 20.Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993;151: 4562–4573. [PubMed] [Google Scholar]
  • 21.Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med. 1998;4: 1020–1024. 10.1038/2006 [DOI] [PubMed] [Google Scholar]
  • 22.Jenkins C, Roberts J, Wilson R, MacLean MA, Shilito J, Walker JJ. Evidence of a T(H) 1 type response associated with recurrent miscarriage. Fertil Steril. 2000;73: 1206–1208. 10.1016/s0015-0282(00)00517-3 [DOI] [PubMed] [Google Scholar]
  • 23.Lissauer D, Goodyear O, Khanum R, Moss PA, Kilby MD. Profile of maternal CD4 T-cell effector function during normal pregnancy and in women with a history of recurrent miscarriage. Clin Sci (Lond). 2014;126: 347–354. 10.1042/CS20130247 [DOI] [PubMed] [Google Scholar]
  • 24.Bharti B, Lee SJ, Lindsay SP, Wingard DL, Jones KL, Lemus H, et al. Disease severity and pregnancy outcomes in women with rheumatoid arthritis: results from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. J Rheumatol. 2015;42: 1376–1382. 10.3899/jrheum.140583 [DOI] [PubMed] [Google Scholar]
  • 25.Fischer-Betz R, Specker C. Pregnancy in systemic lupus erythematosus and antiphospholipid syndrome. Best Pract Res Clin Rheumatol. 2017;31: 397–414. 10.1016/j.berh.2017.09.011 [DOI] [PubMed] [Google Scholar]
  • 26.Sawicki J, Siddha S, Rosen C. Vitiligo and associated autoimmune disease: retrospective review of 300 patients. J Cutan Med Surg. 2012;16: 261–266. 10.1177/120347541201600408 [DOI] [PubMed] [Google Scholar]
  • 27.Vrijman C, Kroon MW, Limpens J, Leeflang MM, Luiten RM, van der Veen JP, et al. The prevalence of thyroid disease in patients with vitiligo: a systematic review. Br J Dermatol. 2012;167: 1224–1235. 10.1111/j.1365-2133.2012.11198.x [DOI] [PubMed] [Google Scholar]
  • 28.Tanemura A, Yajima T, Nakano M, Nishioka M, Itoi S, Kotobuki Y, et al. Seven cases of vitiligo complicated by atopic dermatitis: suggestive new spectrum of autoimmune vitiligo. Eur J Dermatol. 2012;22: 279–280. 10.1684/ejd.2012.1656 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Christy Pu

3 Feb 2021

PONE-D-20-40830

Pregnancy outcomes in women with vitiligo: a Taiwan nationwide cohort study

PLOS ONE

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Academic Editor

PLOS ONE

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Reviewer #1: 1. The study of the relations between pregnant outcomes and vitiligo is quite rare, this research points out some unknown features by applying large scale research database.

2. The Taiwan National Health Insurance (NHI) and the National Health Insurance Research Database (NHIRD) should be different. Are there any references indicating the coverage rate (>99% in the text) and the reimbursement system of NHI? Further, how it works between the NHI and NHIRD? Third, the abbreviation of NHIRD should be used when it first appeared in the manuscript.

3. As mentioned in the study limitation section, the extend and severity of the vitiligo is difficult to be defined, therefore, the treatment of choice remained controversy. Topical agents have longstanding been used as the first line therapy, why only systemic treatments were regarded as preconception treatment? Consequently, should the 800 cases who were assigned as “without treatment” be “real non treatment” or “topical treatment”? Since those cases without treatment also remained controversy, the term used in the table 3 should be revised, and the conclusion also should be reconsidered accordingly.

4. As for the comorbid diseases, the SLE/Sjogren’s syndrome/RA were excluded for the enrollment in the beginning, so how to explain why those diseases still existed in the abortion group of vitiligo patients? Furthermore, immunosuppressive agents such as methotrexate and azathioprine are not common as the systemic medications for vitiligo prescribed by dermatologists, is there any explanation?

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PLoS One. 2021 Mar 22;16(3):e0248651. doi: 10.1371/journal.pone.0248651.r002

Author response to Decision Letter 0

15 Feb 2021

1. The study of the relations between pregnant outcomes and vitiligo is quite rare, this research points out some unknown features by applying large scale research database.

Response:

Thanks for your kind comment. The purpose of our study is to emphasize the importance of vitiligo in pregnant women. Out of personal discussion, most obstetricians would check whether pregnant patients were previously diagnosed as SLE or Sjögren’s syndrome, but vitiligo which is also an autoimmune disease seldom drew their attention. Besides, our study also revealed the importance of disease control with systemic treatment to reduce the risk of miscarriage.

2. The Taiwan National Health Insurance (NHI) and the National Health Insurance Research Database (NHIRD) should be different. Are there any references indicating the coverage rate (>99% in the text) and the reimbursement system of NHI? Further, how it works between the NHI and NHIRD? Third, the abbreviation of NHIRD should be used when it first appeared in the manuscript.

Response:

Thanks for your kind comment and reminder. Taiwan National Health Insurance (NHI) is a single-payer compulsory social insurance. This system promises equal access to healthcare for all citizens, and the coverage had reached 99% [1]. NHIRD, the large computerized databases, derived from the National Health Insurance Administration (the former Bureau of National Health Insurance, BNHI), Ministry of Health and Welfare (the former Department of Health, DOH), Taiwan and maintained by the National Health Research Institutes, Taiwan, are provided to scientists in Taiwan for research purposes. The data in NHIRD is fully anonymized linked information, including outpatient care, inpatient care, emergency care, treatment procedures, and prescription drugs.

3. As mentioned in the study limitation section, the extend and severity of the vitiligo is difficult to be defined, therefore, the treatment of choice remained controversy. Topical agents have longstanding been used as the first line therapy, why only systemic treatments were regarded as preconception treatment? Consequently, should the 800 cases who were assigned as “without treatment” be “real non treatment” or “topical treatment”? Since those cases without treatment also remained controversy, the term used in the table 3 should be revised, and the conclusion also should be reconsidered accordingly.

Response:

Thanks for your kind reminder. As your comment, topical agents have longstanding been used as the first line therapy. In this study, we want to know if the systemic treatment before pregnancy decreases the risk of abortion or not, and we revised our article accordingly, including manuscript and tables.

4. As for the comorbid diseases, the SLE/Sjogren’s syndrome/RA were excluded for the enrollment in the beginning, so how to explain why those diseases still existed in the abortion group of vitiligo patients? Furthermore, immunosuppressive agents such as methotrexate and azathioprine are not common as the systemic medications for vitiligo prescribed by dermatologists, is there any explanation?

Response:

Thanks for your kind comment. This is a retrospective cohort study ranging from January 1st, 2000 to December 31st, 2015. SLE/Sjogren’s syndrome/RA were excluded for the enrollment in the beginning, and we rechecked our enrolled data that no one was diagnosed of SLE/Sjogren’s syndrome/RA before their first pregnancy. We kept following the medical records after their first pregnancy and found the increased risk of SLE/Sjogren’s syndrome/RA in patients with vitiligo who experienced abortion. Besides, steroid phobia is a common problem in my country. Some patients rejected any treatment containing steroid, including topical and oral agents. At that time, we will arrange phototherapy and/or prescribe topical calcineurin inhibitors and/or oral immunosuppressive agents, such as methotrexate and azathioprine, to control their vitiligo disease activity.

Reference

1. Wu T-Y, Majeed A, Kuo KN. An overview of the healthcare system in Taiwan. London journal of primary care. 2010;3(2):115-9.

Attachment

Submitted filename: Reviewer opinion and response.doc

Click here for additional data file. (43KB, doc)

Decision Letter 1

Christy Pu

23 Feb 2021

PONE-D-20-40830R1

Pregnancy outcomes in women with vitiligo: a Taiwanese nationwide cohort study

PLOS ONE

Dear Dr. Hung,

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We look forward to receiving your revised manuscript.

Kind regards,

Christy Pu

Academic Editor

PLOS ONE

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PLoS One. 2021 Mar 22;16(3):e0248651. doi: 10.1371/journal.pone.0248651.r004

Author response to Decision Letter 1

26 Feb 2021

1. Please remove results from Discussion.

Response:

Thanks for your kind comment. The results were removed from discussion in the revised article accordingly.

2. Odds ratios among different studies (or models) should never be compared in terms of magnitudes. This is a common mistake. Please remove all comparisons and rephrase all relevant discussions.

Response:

Thanks for your kind comment and reminder. We revised and rephrased our article accordingly.

3. In the Limitation section, please discuss briefly direction of bias and how they may affect your conclusion.

Response:

Thanks for your kind comment and reminder. We took your recommendation and revised our article accordingly.

Attachment

Submitted filename: Reviewer opinion and response.doc

Click here for additional data file. (33.5KB, doc)

Decision Letter 2

Christy Pu

3 Mar 2021

Pregnancy outcomes in women with vitiligo: a Taiwanese nationwide cohort study

PONE-D-20-40830R2

Dear Dr. Hung,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Christy Pu

Academic Editor

PLOS ONE

Acceptance letter

Christy Pu

12 Mar 2021

PONE-D-20-40830R2

Pregnancy outcomes in women with vitiligo: a Taiwanese nationwide cohort study

Dear Dr. Wang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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Academic Editor

PLOS ONE

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