High-risk groups of Neonatal Lupus Erythematosus in term infants: a birth cohort study

High-risk groups of Neonatal Lupus Erythematosus in term infants: a birth cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article High-risk groups of Neonatal Lupus Erythematosus in term infants: a birth cohort study Ma Jingran, Li Zhenghong, Song Hongmei, Zhang Lejia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3176258/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Oct, 2023 Read the published version in European Journal of Pediatrics → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose: This study aims to analyse the clinical characteristics and risk factors of high-risk groups of neonatal lupus erythematosus (NLE) in term infants. Methods: The high-risk groups of NLE whose mothers were positive of anti-SSA, SSB or U1RNP antibodies during pregnancy were enrolled. They were born from February 2013 to February 2020, with a gestational age not less than 37 weeks. We analyzed their clinical data from birth to 24 months after birth. Results: A total number of 105 cases of NLE high-risk groups were included. Among them, 30 cases were diagnosed with NLE (NLE group) and 75 cases were not (non-NLE group). The affected systems of the NLE group included dermal (13.3%), hepatic (76.0%), and hematological system (43.3%). Hepatic involvement, anemia and thrombocytopenia could not emerge until 60 days, 41 days and 22 days after birth in some cases. The systems involvement could be cured within 3 to 12 months after birth. The clearance time of specific autoantibodies was 12 months after birth. There was no significant difference in clinical characteristics of babies and their mothers between the two groups, neither of the positive rate or clearance time of specific autoantibodies. Conclusion: After standardized prenatal health care, there is still a high risk of dermal, hepatic, or hematological system involvement for high-risk groups of NLE. There are no specific indicators to predict whether the babies will develop to NLE or not. All of them need to be followed up closely within one year after birth. Neonatal lupus erythematosus SSA SSB follow up Introduction Neonatal Lupus Erythematosus (NLE) is a relatively rare acquired autoimmune disease. It is related to the mother's positive autoantibodies to Sjögren’s syndrome types A or B autoantigens (anti-SSA, or SSB), sometimes positive anti-U1 ribonucleoprotein (RNP) antibody, which are transmitted to the fetus through the placenta [1]. Most of the mothers suffer from systemic lupus erythematosus (SLE), Sjogren's Syndrome (SS), rheumatoid arthritis, mixed connective tissue disease, or undifferentiated connective tissue disease, while 25–60% of the mothers are asymptomatic and unaware of their diseases [2]. In addition, 0.1–1.5% of the healthy pregnant women also have positive autoantibodies mentioned above [3,4]. Although NLE is relatively rare, it has a great impact on the health of the fetus and the newborn. High-risk groups of NLE refer to newborns whose mother has positive NLE-specific autoantibodies (anti-SSA and/or anti-SSB and/or RNP), including those diagnosed with NLE and those who do not meet the diagnostic criteria. Mothers with autoimmune diseases may have premature delivery due to their diseases. In view of the complex system involvement of premature infants, which are confounding factors of the system involvement of NLE, we only include full-term infants in this study. More and more high-risk infants of NLE will be born as their mothers’ good disease control. This study aims to evaluate the clinical characteristics of high-risk groups of NLE under current medical interventions, and risk factors of developing NLE, so as to guide the diagnosis and treatment of high-risk infants of NLE. Materials and Methods 1. Research objects Inclusion criteria: Term babies born in our hospital from February 2013 to February 2020 whose mothers had positive NLE-specific autoantibodies (anti-SSA and/or anti-SSB and/or RNP) were included. The birth gestational age was no less than 37 weeks. Exclusion criteria: a. Birth gestational age was less than 37 weeks. B. Babies were suffered from other serious chronic diseases. Diagnostic criteria of the NLE group: The diagnosis of NLE was made when the mother had positive anti-SSA and/or anti-SSB and/or RNP, and fetus or newborn developed atrioventricular heart block, or the newborn had the typical rash (circular erythema or oval erythema) or hepatic (elevated transaminase, cholestasis, liver or spleen enlargement) or hematologic manifestations (anemia, neutrophilia or thrombocytopenia) in the absence of another explanation. Criteria of non-NLE group: The pregnant mothers were positive for anti-SSA and/or anti-SSB and/or RNP antibodies, but the offspring did not meet the diagnostic criteria of NLE. Reference range of indicators and diagnostic criteria of hepatic and hematological system involvement were listed as below. a. Hepatic system: Normal reference value of alanine aminotransferase (ALT): 0-67U/L (within 1 month old), 8–71 U/L (28 days to 1 year old), and 8–42 U/L (1 to 2 years old). Normal reference value of aspartate aminotransferase (AST): 30–100 U/L (boy) and 24–95 U/L (girl) (within 7 days old), 22–71 U/L (8 to 30 days old), 21–80 U/L (28 days to 1 year old), and 22–59 U/L (1 to 2 years old). Normal reference value of glutamate transpeptidase (GGT): 13–147 U/L (within 1 month old), 12–123 U/L (1 to 2 months old), 9-150 U/L (28 days to 6 months old), 6–31 U/L (6 months to 1 year old), and 5–19 U/L (1 to 2 years old). Normal reference value of alkaline phosphatase (ALP): 34–114 U/L (within 1 month old), 98–532 U/L (28 days to 6 months old), 106–420 U/L (6 months to 1 year old), and 128–432 U/L (1 to 2 years old) [6,7]. b. Hematological system: Anemia: haemoglobin (Hb) < 145g/L (within 2 weeks old), < 110g/L (2 weeks to 1 month old), < 90g/L (1 to 4 months old), < 100g/L (4 to 6 months old), and < 110g/L (6 months to 2 years old) [6,8]. Thrombocytopenia: Platelet < 150×10S9/L. Normal reference values for neutrophils: 0.6–7.1×10S9/L (28 days to 6 months old), 0.8–6.1×10S9/L (6 months to 1 year old), and 0.9–5.5×10S9/L (1 to 2 years old) [9]. 2. Research methods: Collecting clinical data of NLE high-risk populations from birth to 24 months after birth for retrospective cohort study. The data included: a. gestational age, birth weight, length, and head circumference. b. rash examination, blood routine test, liver function test, electrocardiogram, echocardiogram, and NLE-specific autoantibodies test. c. mothers’ age, delivery mode, abnormal child-bearing history, the usage of prednisone or hydroxychloroquine during pregnancy, and mothers’ NLE-specific autoantibodies test. 3. Statistical analysis: Continuous variables were expressed as mean ± standard deviation which correspond to normal distribution, and median (25 percentile/75 percentile) which correspond to non-normal distribution. Continuous data were analyzed using Mann–Whitney U test; categorical variables were examined using Fisher’s exact test. And P value < 0.05 was considered significant. SPSS for Windows version 23 software (SPSS Inc., Chicago, IL, USA) was used. Results 1. Basic information: A total of 105 cases were included as high-risk groups of NLE, with a gestational age of 38 weeks 4 days ± 6 days (37 weeks to 40 weeks 2 days), a birth weight of 3003 ± 343 (2170–3840) g, a birth length of 49.0 (48.0/50.0, 44.0–53.0)cm, and a birth circumference of 34.0 (33.1/34.5, 32.0–43.0)cm. Among them, 30 cases were diagnosed with NLE (NLE group) and 75 cases were not diagnosed with NLE (non-NLE group). Their mothers were 31 ± 4 (22–43) years old, and cesarean sections accounted for 51.4%. The abnormal child-bearing history included: 1 case of labor induction for fetal bradycardia, 2 cases of labor inductions for mothers’ poor disease control, 4 cases of embryo damage, 4 cases of spontaneous abortion (excluding biochemical pregnancy), and 1 case of ectopic pregnancy in the NLE group. And 1 case of labor induction for fetal III° atrioventricular block (twice in this case), 1 case of labor induction for fetal heart deformation and atrioventricular block, 4 cases of labor inductions for mothers’ poor disease control, 3 cases of fetal death, 11 cases of embryo damage, 1 case of labor induction for fetal abdominal cyst, 1 case of trisomy 21 syndrome delivery, 5 cases of spontaneous abortions (excluding biochemical pregnancy), and 1 case of hydatidiformatitus in the non-NLE group. There was no significant difference in gestational age, birth weight, length, head circumference, mothers’ age, delivery mode, abnormal child-bearing history, or the usage of prednisone or hydroxychloroquine during pregnancy between the two groups, which was shown in Table 1 . Table 1 Comparison of basic information between NLE group and non-NLE group NLE group (N = 30) Non-NLE group (N = 75) P value Gestational age 38 weeks 5 days ± 5 days (37 weeks- 40 weeks) 38 weeks 4 days ± 6 days (37 weeks- 40 weeks 2 days) 0.546 Birth weight (g) 3023 ± 344 (2260–3760) 2996 ± 345 (2170–3840) 0.650 Length (cm) 49 ± 1.7 (45–53) 48.2 (48/49, 44-52.5) 0.155 Head circumference (cm) 34 (33.5/34.8, 32–43) 33.9 ± 1 (32–37) 0.618 Mother’s age (years old) 32 ± 4(25–39) 31 ± 4(22–43) 0.669 Delivery mode(caesarean section: vaginal delivery) 1:1 12:13 1.000 Abnormal child-bearing history (yes: no) 1:2 21:53 0.641 Usage of prednisone during pregnancy (yes: no) 11:4 2:1 0.643 The maintenance dose of prednisone during pregnancy (pills/day) 1.5(1/2, 0.25-10) 1.5(1/2, 0.5-6) 0.531 Usage of hydroxychloroquine during pregnancy (yes: no) 14:1 23:2 1.000 2. Systems involvement: The affected systems of the NLE group included dermal (4/30 = 13.3%), hepatic (19/25 = 76.0%), and hematological system (13/30 = 43.3%). The emerging time of typical rash was 16.5 ± 10.9 days after birth. Hepatic involvement, anemia and thrombocytopenia could not emerge until at most 60 days, 41 days and 22 days after birth in some cases. Most of the system involvement could return to normal after observation, but some of them required active intervention, such as the application of topical hormones, liver-protecting drugs, iron supplements, and human immunoglobulin. All of the skin involvement could recover. The hematological system involvement could be cured within 3 months after birth, and hepatic involvement within 12 months. More details were shown in Table 2 . Table 2 Systems involvement in NLE group Systems involved N (percentage) Emerging time (days after birth) Treatment Recovery time (days after birth) Typical rash 4 (13.3%) 16.5 ± 10.9 (5–30) 2 cases with topical hormones 7 days for 1 case ALT elevation 2 (8%) 15、60 2 cases with liver-protecting drugs 28、120 AST elevation 10 (40%) 2 (2/5, 2–60) 3 cases with liver-protecting drugs 28、150、180 GGT elevation 17 (68%) 2 (2/2, 2–15) None 105 (29/180, 28–180) TBA elevation 2 (8%) 14、15 2 cases with cholagogic drugs 28、360 Anemia 9 (30%) 6 (5/7, 2–41) 5 cases with iron supplements 28 ± 24 (3–67) Thrombocytopenia 3 (10%) 1、5、22 1 case with human immunoglobulin (PLT 35*10 9 /L after birth) 8、30、90 Neutropenia 1 (3.3%) 56 None 90 3. Autoantibodies For infants who did not test their own antibodies after birth (1 case in the NLE group and 19 cases in the non-NLE group) or infants whose NLE-specific antibodies were all negative (7 cases in the NLE group and 3 cases in the non-NLE group, probably caused by detection errors by different test methods), we treated their mothers’ antibodies types as the infants’. There was no significant difference in positive rates of SSA antibody (27/30, 90.0% vs 72/75, 96.0%, P = 0.350), SSB antibody (7/30, 23.3% vs 18/75, 24.0%, P = 1.000) or RNP antibody (12/30, 40.0% vs 22/75, 29.3%, P = 0.357) between the NLE group and non-NLE group. As to the amount of positive antibodies, there was no significant difference in single antibody positive (15/30, 50.0% vs 43/75, 57.3%, P = 0.522), double antibodies positive (14/30, 46.7% vs 28/75, 37.3%, P = 0.388) or triple antibodies positive (1/30, 3.33% vs 4/75, 5.33%, P = 1.000) between the NLE group and non-NLE group. The comparison of autoantibodies were shown in Table 3 . Table 3 Comparison of autoantibodies between NLE group and non-NLE group Positive antibody types Single SSA (N) Single SSB (N) Single RNP (N) SSA and SSB (N) SSA and RNP (N) SSB and RNP (N) SSA, SSB and RNP (N) NLE group 12 0 3 6 8 0 1 Non-NLE group 40 0 3 14 14 0 4 P value 0.281 - 0.350 1.000 0.428 - 1.000 In the NLE group, 29 cases (29/30 = 96.7%) were followed up to a median time of 18 months after birth (3.5/24 months, 1.5–24 months), of which 14 cases were followed up to 24 months after birth. In the non-NLE group, 66 cases (66/75 = 88.0%) were followed up to a median time of 12 months after birth (3.5/24 months, 0.5–24 months), of which 21 cases were followed up to 24 months after birth. There was no significant difference in the follow-up time between the two groups (P = 0.347). In the NLE group, 11 cases monitored their autoantibodies during follow up. Among them, the autoantibodies turned negative in 8 cases within a median time of 10.3 months (9.0/13.0 months, 6–15 months) after birth, while in the other 3 cases, the autoantibodies were still positive in 4 months (RNP), 6 months (SSA) and 12 months (SSA) after birth respectively, and they didn’t test the autoantibodies anymore within 24 months after birth. In the non-NLE group, 26 cases monitored the autoantibodies. In 22 cases of them, the autoantibodies turned negative within a median time of 12.0 months (9.0/12.3 months, 6–23 months) after birth, while 4 cases still had positive autoantibodies in 2–6 months (SSA and RNP) after birth, and they did not re-examine the autoantibodies within 24 months after birth. There was no significant difference in the disappearing time of autoantibodies between the two groups (P = 0.615). The disappearing time of autoantibodies were shown in Table 4 . Table 4 Comparison of disappearing time of autoantibodies between NLE group and non-NLE group SSA (months after birth) SSB (months after birth) RNP (months after birth) All autoantibodies (months after birth) NLE group 9 (9/13, 6–15) 6、15 11.1 ± 2 (9–13) 10.3 (9/13, 6–15) Non-NLE group 12 (9/12, 6–18) 9.8 ± 2.9 (6–12) 11.6 ± 5.2 (6–23) 12 (9/12.3, 6–23) All infants 12 (9/12, 6–18) 10 ± 3.6 (6–15) 12 (9/12.5, 6–23) 12 (9/13, 6–23) P value 0.516 0.812 0.765 0.615 Discussion Studies have shown that when the mother’s NLE-specific autoantibodies are positive, the risk of giving birth to a child with NLE is 1%-2%. However, the risk will increase to 17%-20% if the previous babies are suffered from NLE [5,10,11,12], but the data are not consistent according to different research, ranging from 25–33% [13]. In our study, infants diagnosed with NLE account to 28.6% (30/105) in high risk populations whose mothers are positive for NLE-specific autoantibodies, which is higher than in previous studies. The first reason is probably that the diagnostic criteria of NLE are different in different studies. There is no definite diagnostic criteria for NLE. In order to facilitate registration of NLE, the Research Registry for Neonatal Lupus in the United States only took children with congenital heart block (CHB) or typical skin rash into consideration [14]. The lower risks they mentioned mainly refer to the risk of developing CHB, not the other systems involvement. While other researchers took hematological and hepatic systems involvement into account as a part of the diagnostic criteria [5]. After standardized prenatal health care, the risk of CHB may decrease dramatically, but there is still a high risk of dermal, hepatic, or hematological system involvement, some of which require active intervention and may increase the risk of NLE of the next child. So we also adopt the diagnostic criteria which includes hematological and hepatic systems involvement in addition to CHB and dermal manifestations, for the purpose of identifying potential NLE babies. The second reason of higher risk of NLE in our study is possibly that mothers have more abnormal child-bearing histories. Up to 40.0% (12/30) of the mothers in the NLE group had abnormal child-bearing histories, such as labor induction for fetal bradycardia, with the possibility of carrying a NLE fetus before and resulting in an increased risk of NLE for the next pregnancy. NLE can affect the cardiac system which mostly manifest cardiac block, and the other systems such as dermal, hepatic, hematological and sometimes central nervous system [15]. Poor prognosis is seen in cardiac block patients [5]. No cardiac block babies were born in our study, which might be related to the standardized prenatal health care and intervention in our hospital by good multi-department cooperation. Besides cardiac system, the most common manifestations are glutamate transpeptidase (GGT) elevation (68%), aspartate aminotransferase (AST) elevation (40%), anemia (30%), and skin rash (13.3%) in the other affected systems, while thrombocytopenia (10%), alanine aminotransferase (ALT) elevation (8%), total bile acid (TBA) elevation (8%) and neutropenia (3.3%) are relatively rare. Previous studies have indicated that dermal system involvement is seen in 4%-16% of anti-Ro (SSA) antibodies and/or anti-La (SSB) antibodies exposed infants [16,17,18,19], which is consistent with our study. In some cases, there is a skin rash right after birth, but the rash may also occur several days later after exposure to ultraviolet light, which may cause or aggravate the rash. In a cohort study of 57 infants, rashes can be recognized at an average time of 6 weeks after birth [21]. In our study, the appearance time of rash was 16.5 days after birth in average. None appeared immediately after birth, with the earliest appearance time of 5 days, and latest of 30 days after birth. Other systems involvement can occur with no obvious symptoms, including thrombocytopenia in 1–22 days after birth, and anemia, neutropenia and liver enzymes elevation within 2–3 months after birth, which need to pay more attention. Therefore we recommend to monitor closely the hepatic and hematological system within 2–3 months after birth, and treat the patients if necessary. Similar to our data, a follow-up study of infants who had positive anti-SSA antibodies found that some patients developed NLE during follow-up, whose hematological system was involed as anemia, neutropenia, or thrombocytopenia without symptoms. About 56% of cases showed mild and temporary transaminase elevation in 3 months after birth. So researchers recommend clinical and laboratory examinations at the age of 3 months after birth, because hepatic and hematological systems are most probably affected at this time point [22]. As children grow up, the specific autoantibodies taken from their mothers gradually turn negative, and the NLE symptoms and signs also gradually disappear except for cardiac block [22]. The prognosis is good for children with dermal, hepatic or haematological systems involvement. A follow-up study of infants whose mothers had positive anti-SSA antibodies found that a majority of hematological system involvement recovered completely within 9 months after birth [22]. In our study, the hematological system involvement could recover within 3 months after birth. The hepatic system involvement could all recover within 12 months, and mostly 6 months after birth. But some of the conditions were serious and required timely and active intervention, such as thrombocytopenia. In a severe case, platelet (PLT) could be reduced to 35*109/L due to NLE. Researchers have found that the anti-SSA of 10% of the infants whose mothers have positive anti-SSA are still positive at the age of 9 months [22]. We have found that the median time for anti-SSA, SSB and RNP antibodies to turn negative is 12 months after birth. What’s more, the involved systems of NLE patients, especially hepatic system, may not recover until 12 months after birth for some babies. So we recommend that the high-risk babies of NLE to be followed up until at least 12 months after birth. Studies have shown that young mother, first child and lack of glucocorticoid therapy may be risk factors to increase the risk of NLE of the offspring [23]. Other studies believe that the interaction of genetic susceptibility, intrauterine environment and maternal antibodies is more complex than currently known [24]. We have found that there is no significant difference between the NLE group and the non-NLE group in mothers’ age, delivery mode, abnormal child-bearing history, or the usage of prednisone or hydroxychloroquine during pregnancy, neither of the kinds and amounts of positive autoantibodies, indicating that no single factor can affect the systems involvement of NLE except for cardiac block. There are some limitations in this study. First of all, our study is a single-center study. Due to the standardized prenatal health care in our center, no neonates have cardiac block in this study. Secondly, this study only includes full-term infants. Thirdly, babies are followed up to 24 months after birth in our study, and more follow-up studies are still needed for the long-term prognosis of high-risk groups of NLE. In conclusion, the dermal, hepatic, and hematological systems involvement of NLE can gradually appear during follow-up. The affected systems can recover with a good prognosis, but some of the conditions are serious and require timely and active intervention. No single factor has been found to predict whether the high-risk offspring will suffer from NLE or not. Therefore, for all the high-risk populations of NLE, it is necessary to follow up closely within one year after birth, paying attention to the dermal, hepatic, and hematological systems involvement and monitoring their autoantibodies. Abbreviations ALP : Alkaline phosphatase ALT : Alanine aminotransferase AST : Aspartate aminotransferase CHB : Congenital heart block GGT : Glutamate transpeptidase NLE : Neonatal lupus erythematosus PLT : Platelet RNP : Ribonucleoprotein SLE : Systemic lupus erythematosus SS : Sjogren's Syndrome SSA : Sjögren’s syndrome types A autoantigens SSB : Sjögren’s syndrome types B autoantigens TBA : Total bile acid Declarations Funding This study was funded by Ministry of Science and Technology of the People's Republic of China, National Key Research and Development Program of China. Grant number: 2021YFC2702004. Competing Interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions Li Zhenghong and Song Hongmei initiated and supervised this research. Ma Jingran and Zhang Lejia performed the study. Ma Jingran analyzed the data, wrote the manuscript and prepared the figures. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Institutional Review Board of Peking Union Medical College Hospital. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish The authors affirm that consent to publish has been received from all participants. References Heelan K, Watson R, Collins SM (2013) Neonatal lupus syndrome associated with ribonucleoprotein antibodies. Pediatr Dermatol 30: 416–423. https://doi:10.1111/pde.12088 Savino F, Viola S, Tarasco V, Locatelli E, Ricagni A, Coppo P (2016) Neonatal lupus erythematosus: a cutaneous cases based update. Ital J Pediatr 42:1–5. https://doi:10.1186/s13052-015-0208-5 Satoh M, Chan EK, Ho LA, et al (2012) Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. 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Cite Share Download PDF Status: Published Journal Publication published 17 Oct, 2023 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Major revision 15 Sep, 2023 Reviews received at journal 07 Sep, 2023 Reviewers agreed at journal 28 Aug, 2023 Reviewers invited by journal 19 Jul, 2023 Editor assigned by journal 18 Jul, 2023 Submission checks completed at journal 18 Jul, 2023 First submitted to journal 16 Jul, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3176258","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":219704616,"identity":"f7908d48-978d-495b-bc35-e409a4bfebc6","order_by":0,"name":"Ma Jingran","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ma","middleName":"","lastName":"Jingran","suffix":""},{"id":219704617,"identity":"a9915a77-340f-4a79-b24d-2c94bcd45711","order_by":1,"name":"Li Zhenghong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYHACxgM8BRIMBkAWM0MFkGQHCjUQ0HOAxwCm5QwDAw8zcVoYIFoY24jQYnC898GBNwYW9ubsvYdfF86zSdzPzHzw4QwGOzldHPoMzhw3ODjHQILZsudcmvXMbWmJPcxsyYYbGJKNzQ5g12J2I43hMNAvbAY3csyMebcdBmrhMZN8wHAgcRsBLTwG998AtcwhQYuEwQ0e48e8DVAtG/BosT9zjAHkFwODMzlmzDzH0ox7DgP9MsMAt18k29sYH7ypqLM3OH7G+DNPjY1se3vzwYc9FXZyuLQgAzYJBNuAsHIQYP5AnLpRMApGwSgYaQAAicJZ2amtWe4AAAAASUVORK5CYII=","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Zhenghong","suffix":""},{"id":219704618,"identity":"56ebe82c-cad8-4c3c-88d7-413780818795","order_by":2,"name":"Song Hongmei","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Song","middleName":"","lastName":"Hongmei","suffix":""},{"id":219704619,"identity":"569be053-84c5-4ce1-8753-1962ed4b7382","order_by":3,"name":"Zhang Lejia","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Lejia","suffix":""}],"badges":[],"createdAt":"2023-07-17 02:59:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3176258/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3176258/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-023-05283-8","type":"published","date":"2023-10-17T15:01:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":45090867,"identity":"aecd7393-791d-459c-9ea6-a1b55f4933e4","added_by":"auto","created_at":"2023-10-23 15:06:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":255901,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3176258/v1/8375e28b-660f-4b13-80ef-3fa96252ab97.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"High-risk groups of Neonatal Lupus Erythematosus in term infants: a birth cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeonatal Lupus Erythematosus (NLE) is a relatively rare acquired autoimmune disease. It is related to the mother's positive autoantibodies to Sj\u0026ouml;gren\u0026rsquo;s syndrome types A or B autoantigens (anti-SSA, or SSB), sometimes positive anti-U1 ribonucleoprotein (RNP) antibody, which are transmitted to the fetus through the placenta [1]. Most of the mothers suffer from systemic lupus erythematosus (SLE), Sjogren's Syndrome (SS), rheumatoid arthritis, mixed connective tissue disease, or undifferentiated connective tissue disease, while 25\u0026ndash;60% of the mothers are asymptomatic and unaware of their diseases [2]. In addition, 0.1\u0026ndash;1.5% of the healthy pregnant women also have positive autoantibodies mentioned above [3,4]. Although NLE is relatively rare, it has a great impact on the health of the fetus and the newborn.\u003c/p\u003e \u003cp\u003eHigh-risk groups of NLE refer to newborns whose mother has positive NLE-specific autoantibodies (anti-SSA and/or anti-SSB and/or RNP), including those diagnosed with NLE and those who do not meet the diagnostic criteria. Mothers with autoimmune diseases may have premature delivery due to their diseases. In view of the complex system involvement of premature infants, which are confounding factors of the system involvement of NLE, we only include full-term infants in this study.\u003c/p\u003e \u003cp\u003eMore and more high-risk infants of NLE will be born as their mothers\u0026rsquo; good disease control. This study aims to evaluate the clinical characteristics of high-risk groups of NLE under current medical interventions, and risk factors of developing NLE, so as to guide the diagnosis and treatment of high-risk infants of NLE.\u003c/p\u003e "},{"header":"Materials and Methods","content":"\u003cp\u003e1. Research objects\u003c/p\u003e\n\u003cp\u003eInclusion criteria: Term babies born in our hospital from February 2013 to February 2020 whose mothers had positive NLE-specific autoantibodies (anti-SSA and/or anti-SSB and/or RNP) were included. The birth gestational age was no less than 37 weeks.\u003c/p\u003e\n\u003cp\u003eExclusion criteria: a. Birth gestational age was less than 37 weeks. B. Babies were suffered from other serious chronic diseases.\u003c/p\u003e\n\u003cp\u003eDiagnostic criteria of the NLE group: The diagnosis of NLE was made when the mother had positive anti-SSA and/or anti-SSB and/or RNP, and fetus or newborn developed atrioventricular heart block, or the newborn had the typical rash (circular erythema or oval erythema) or hepatic (elevated transaminase, cholestasis, liver or spleen enlargement) or hematologic manifestations (anemia, neutrophilia or thrombocytopenia) in the absence of another explanation.\u003c/p\u003e\n\u003cp\u003eCriteria of non-NLE group: The pregnant mothers were positive for anti-SSA and/or anti-SSB and/or RNP antibodies, but the offspring did not meet the diagnostic criteria of NLE.\u003c/p\u003e\n\u003cp\u003eReference range of indicators and diagnostic criteria of hepatic and hematological system involvement were listed as below. a. Hepatic system: Normal reference value of alanine aminotransferase (ALT): 0-67U/L (within 1 month old), 8\u0026ndash;71 U/L (28 days to 1 year old), and 8\u0026ndash;42 U/L (1 to 2 years old). Normal reference value of aspartate aminotransferase (AST): 30\u0026ndash;100 U/L (boy) and 24\u0026ndash;95 U/L (girl) (within 7 days old), 22\u0026ndash;71 U/L (8 to 30 days old), 21\u0026ndash;80 U/L (28 days to 1 year old), and 22\u0026ndash;59 U/L (1 to 2 years old). Normal reference value of glutamate transpeptidase (GGT): 13\u0026ndash;147 U/L (within 1 month old), 12\u0026ndash;123 U/L (1 to 2 months old), 9-150 U/L (28 days to 6 months old), 6\u0026ndash;31 U/L (6 months to 1 year old), and 5\u0026ndash;19 U/L (1 to 2 years old). Normal reference value of alkaline phosphatase (ALP): 34\u0026ndash;114 U/L (within 1 month old), 98\u0026ndash;532 U/L (28 days to 6 months old), 106\u0026ndash;420 U/L (6 months to 1 year old), and 128\u0026ndash;432 U/L (1 to 2 years old) [6,7]. b. Hematological system: Anemia: haemoglobin (Hb)\u0026thinsp;\u0026lt;\u0026thinsp;145g/L (within 2 weeks old), \u0026lt;\u0026thinsp;110g/L (2 weeks to 1 month old), \u0026lt;\u0026thinsp;90g/L (1 to 4 months old), \u0026lt;\u0026thinsp;100g/L (4 to 6 months old), and \u0026lt;\u0026thinsp;110g/L (6 months to 2 years old) [6,8]. Thrombocytopenia: Platelet\u0026thinsp;\u0026lt;\u0026thinsp;150\u0026times;10S9/L. Normal reference values for neutrophils: 0.6\u0026ndash;7.1\u0026times;10S9/L (28 days to 6 months old), 0.8\u0026ndash;6.1\u0026times;10S9/L (6 months to 1 year old), and 0.9\u0026ndash;5.5\u0026times;10S9/L (1 to 2 years old) [9].\u003c/p\u003e\n\u003cp\u003e2. Research methods: Collecting clinical data of NLE high-risk populations from birth to 24 months after birth for retrospective cohort study. The data included: a. gestational age, birth weight, length, and head circumference. b. rash examination, blood routine test, liver function test, electrocardiogram, echocardiogram, and NLE-specific autoantibodies test. c. mothers\u0026rsquo; age, delivery mode, abnormal child-bearing history, the usage of prednisone or hydroxychloroquine during pregnancy, and mothers\u0026rsquo; NLE-specific autoantibodies test.\u003c/p\u003e\n\u003cp\u003e3. Statistical analysis: Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation which correspond to normal distribution, and median (25 percentile/75 percentile) which correspond to non-normal distribution. Continuous data were analyzed using Mann\u0026ndash;Whitney U test; categorical variables were examined using Fisher\u0026rsquo;s exact test. And P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. SPSS for Windows version 23 software (SPSS Inc., Chicago, IL, USA) was used.\u003c/p\u003e\n"},{"header":"Results","content":"\u003cp\u003e1. Basic information:\u003c/p\u003e\n\u003cp\u003eA total of 105 cases were included as high-risk groups of NLE, with a gestational age of 38 weeks 4 days\u0026thinsp;\u0026plusmn;\u0026thinsp;6 days (37 weeks to 40 weeks 2 days), a birth weight of 3003\u0026thinsp;\u0026plusmn;\u0026thinsp;343 (2170\u0026ndash;3840) g, a birth length of 49.0 (48.0/50.0, 44.0\u0026ndash;53.0)cm, and a birth circumference of 34.0 (33.1/34.5, 32.0\u0026ndash;43.0)cm. Among them, 30 cases were diagnosed with NLE (NLE group) and 75 cases were not diagnosed with NLE (non-NLE group).\u003c/p\u003e\n\u003cp\u003eTheir mothers were 31\u0026thinsp;\u0026plusmn;\u0026thinsp;4 (22\u0026ndash;43) years old, and cesarean sections accounted for 51.4%. The abnormal child-bearing history included: 1 case of labor induction for fetal bradycardia, 2 cases of labor inductions for mothers\u0026rsquo; poor disease control, 4 cases of embryo damage, 4 cases of spontaneous abortion (excluding biochemical pregnancy), and 1 case of ectopic pregnancy in the NLE group. And 1 case of labor induction for fetal III\u0026deg; atrioventricular block (twice in this case), 1 case of labor induction for fetal heart deformation and atrioventricular block, 4 cases of labor inductions for mothers\u0026rsquo; poor disease control, 3 cases of fetal death, 11 cases of embryo damage, 1 case of labor induction for fetal abdominal cyst, 1 case of trisomy 21 syndrome delivery, 5 cases of spontaneous abortions (excluding biochemical pregnancy), and 1 case of hydatidiformatitus in the non-NLE group.\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in gestational age, birth weight, length, head circumference, mothers\u0026rsquo; age, delivery mode, abnormal child-bearing history, or the usage of prednisone or hydroxychloroquine during pregnancy between the two groups, which was shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparison of basic information between NLE group and non-NLE group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNLE group (N\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNon-NLE group (N\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestational age\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 weeks 5 days\u0026thinsp;\u0026plusmn;\u0026thinsp;5 days (37 weeks- 40 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 weeks 4 days\u0026thinsp;\u0026plusmn;\u0026thinsp;6 days (37 weeks- 40 weeks 2 days)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.546\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight (g)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3023\u0026thinsp;\u0026plusmn;\u0026thinsp;344 (2260\u0026ndash;3760)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2996\u0026thinsp;\u0026plusmn;\u0026thinsp;345 (2170\u0026ndash;3840)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.650\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLength (cm)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 (45\u0026ndash;53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48.2 (48/49, 44-52.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.155\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHead circumference (cm)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (33.5/34.8, 32\u0026ndash;43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1 (32\u0026ndash;37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.618\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMother\u0026rsquo;s age (years old)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u0026thinsp;\u0026plusmn;\u0026thinsp;4(25\u0026ndash;39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u0026thinsp;\u0026plusmn;\u0026thinsp;4(22\u0026ndash;43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.669\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDelivery mode(caesarean section: vaginal delivery)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1:1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12:13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbnormal child-bearing history (yes: no)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1:2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21:53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.641\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUsage of prednisone during pregnancy (yes: no)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11:4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2:1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.643\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThe maintenance dose of prednisone during pregnancy (pills/day)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5(1/2, 0.25-10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5(1/2, 0.5-6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.531\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUsage of hydroxychloroquine during pregnancy (yes: no)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14:1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23:2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2. Systems involvement:\u003c/p\u003e\n\u003cp\u003eThe affected systems of the NLE group included dermal (4/30\u0026thinsp;=\u0026thinsp;13.3%), hepatic (19/25\u0026thinsp;=\u0026thinsp;76.0%), and hematological system (13/30\u0026thinsp;=\u0026thinsp;43.3%). The emerging time of typical rash was 16.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 days after birth. Hepatic involvement, anemia and thrombocytopenia could not emerge until at most 60 days, 41 days and 22 days after birth in some cases.\u003c/p\u003e\n\u003cp\u003eMost of the system involvement could return to normal after observation, but some of them required active intervention, such as the application of topical hormones, liver-protecting drugs, iron supplements, and human immunoglobulin. All of the skin involvement could recover. The hematological system involvement could be cured within 3 months after birth, and hepatic involvement within 12 months.\u003c/p\u003e\n\u003cp\u003eMore details were shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSystems involvement in NLE group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSystems involved\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eN (percentage)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEmerging time (days after birth)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTreatment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRecovery time (days after birth)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTypical rash\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (13.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 (5\u0026ndash;30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 cases with topical hormones\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 days for 1 case\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eALT elevation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15、60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 cases with liver-protecting drugs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28、120\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAST elevation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (40%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (2/5, 2\u0026ndash;60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 cases with liver-protecting drugs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28、150、180\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGGT elevation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (68%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (2/2, 2\u0026ndash;15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 (29/180, 28\u0026ndash;180)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTBA elevation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14、15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 cases with cholagogic drugs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28、360\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnemia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (30%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (5/7, 2\u0026ndash;41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 cases with iron supplements\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;24 (3\u0026ndash;67)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThrombocytopenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (10%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1、5、22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 case with human immunoglobulin (PLT 35*10\u003csup\u003e9\u003c/sup\u003e/L after birth)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8、30、90\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeutropenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (3.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e3. Autoantibodies\u003c/p\u003e\n\u003cp\u003eFor infants who did not test their own antibodies after birth (1 case in the NLE group and 19 cases in the non-NLE group) or infants whose NLE-specific antibodies were all negative (7 cases in the NLE group and 3 cases in the non-NLE group, probably caused by detection errors by different test methods), we treated their mothers\u0026rsquo; antibodies types as the infants\u0026rsquo;. There was no significant difference in positive rates of SSA antibody (27/30, 90.0% vs 72/75, 96.0%, P\u0026thinsp;=\u0026thinsp;0.350), SSB antibody (7/30, 23.3% vs 18/75, 24.0%, P\u0026thinsp;=\u0026thinsp;1.000) or RNP antibody (12/30, 40.0% vs 22/75, 29.3%, P\u0026thinsp;=\u0026thinsp;0.357) between the NLE group and non-NLE group. As to the amount of positive antibodies, there was no significant difference in single antibody positive (15/30, 50.0% vs 43/75, 57.3%, P\u0026thinsp;=\u0026thinsp;0.522), double antibodies positive (14/30, 46.7% vs 28/75, 37.3%, P\u0026thinsp;=\u0026thinsp;0.388) or triple antibodies positive (1/30, 3.33% vs 4/75, 5.33%, P\u0026thinsp;=\u0026thinsp;1.000) between the NLE group and non-NLE group. The comparison of autoantibodies were shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparison of autoantibodies between NLE group and non-NLE group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePositive antibody types\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSingle SSA (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSingle SSB (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSingle RNP (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSSA and SSB (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSSA and RNP (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSSB and RNP (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSSA, SSB and RNP (N)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLE group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNon-NLE group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.281\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.350\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.428\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn the NLE group, 29 cases (29/30\u0026thinsp;=\u0026thinsp;96.7%) were followed up to a median time of 18 months after birth (3.5/24 months, 1.5\u0026ndash;24 months), of which 14 cases were followed up to 24 months after birth. In the non-NLE group, 66 cases (66/75\u0026thinsp;=\u0026thinsp;88.0%) were followed up to a median time of 12 months after birth (3.5/24 months, 0.5\u0026ndash;24 months), of which 21 cases were followed up to 24 months after birth. There was no significant difference in the follow-up time between the two groups (P\u0026thinsp;=\u0026thinsp;0.347).\u003c/p\u003e\n\u003cp\u003eIn the NLE group, 11 cases monitored their autoantibodies during follow up. Among them, the autoantibodies turned negative in 8 cases within a median time of 10.3 months (9.0/13.0 months, 6\u0026ndash;15 months) after birth, while in the other 3 cases, the autoantibodies were still positive in 4 months (RNP), 6 months (SSA) and 12 months (SSA) after birth respectively, and they didn\u0026rsquo;t test the autoantibodies anymore within 24 months after birth. In the non-NLE group, 26 cases monitored the autoantibodies. In 22 cases of them, the autoantibodies turned negative within a median time of 12.0 months (9.0/12.3 months, 6\u0026ndash;23 months) after birth, while 4 cases still had positive autoantibodies in 2\u0026ndash;6 months (SSA and RNP) after birth, and they did not re-examine the autoantibodies within 24 months after birth. There was no significant difference in the disappearing time of autoantibodies between the two groups (P\u0026thinsp;=\u0026thinsp;0.615). The disappearing time of autoantibodies were shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparison of disappearing time of autoantibodies between NLE group and non-NLE group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSSA (months after birth)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSSB (months after birth)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRNP (months after birth)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAll autoantibodies (months after birth)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLE group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (9/13, 6\u0026ndash;15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6、15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2 (9\u0026ndash;13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.3 (9/13, 6\u0026ndash;15)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNon-NLE group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (9/12, 6\u0026ndash;18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 (6\u0026ndash;12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 (6\u0026ndash;23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (9/12.3, 6\u0026ndash;23)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAll infants\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (9/12, 6\u0026ndash;18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 (6\u0026ndash;15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (9/12.5, 6\u0026ndash;23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (9/13, 6\u0026ndash;23)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.516\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.812\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.765\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.615\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eStudies have shown that when the mother\u0026rsquo;s NLE-specific autoantibodies are positive, the risk of giving birth to a child with NLE is 1%-2%. However, the risk will increase to 17%-20% if the previous babies are suffered from NLE [5,10,11,12], but the data are not consistent according to different research, ranging from 25\u0026ndash;33% [13]. In our study, infants diagnosed with NLE account to 28.6% (30/105) in high risk populations whose mothers are positive for NLE-specific autoantibodies, which is higher than in previous studies. The first reason is probably that the diagnostic criteria of NLE are different in different studies. There is no definite diagnostic criteria for NLE. In order to facilitate registration of NLE, the Research Registry for Neonatal Lupus in the United States only took children with congenital heart block (CHB) or typical skin rash into consideration [14]. The lower risks they mentioned mainly refer to the risk of developing CHB, not the other systems involvement. While other researchers took hematological and hepatic systems involvement into account as a part of the diagnostic criteria [5]. After standardized prenatal health care, the risk of CHB may decrease dramatically, but there is still a high risk of dermal, hepatic, or hematological system involvement, some of which require active intervention and may increase the risk of NLE of the next child. So we also adopt the diagnostic criteria which includes hematological and hepatic systems involvement in addition to CHB and dermal manifestations, for the purpose of identifying potential NLE babies. The second reason of higher risk of NLE in our study is possibly that mothers have more abnormal child-bearing histories. Up to 40.0% (12/30) of the mothers in the NLE group had abnormal child-bearing histories, such as labor induction for fetal bradycardia, with the possibility of carrying a NLE fetus before and resulting in an increased risk of NLE for the next pregnancy.\u003c/p\u003e\n\u003cp\u003eNLE can affect the cardiac system which mostly manifest cardiac block, and the other systems such as dermal, hepatic, hematological and sometimes central nervous system [15]. Poor prognosis is seen in cardiac block patients [5]. No cardiac block babies were born in our study, which might be related to the standardized prenatal health care and intervention in our hospital by good multi-department cooperation.\u003c/p\u003e\n\u003cp\u003eBesides cardiac system, the most common manifestations are glutamate transpeptidase (GGT) elevation (68%), aspartate aminotransferase (AST) elevation (40%), anemia (30%), and skin rash (13.3%) in the other affected systems, while thrombocytopenia (10%), alanine aminotransferase (ALT) elevation (8%), total bile acid (TBA) elevation (8%) and neutropenia (3.3%) are relatively rare. Previous studies have indicated that dermal system involvement is seen in 4%-16% of anti-Ro (SSA) antibodies and/or anti-La (SSB) antibodies exposed infants [16,17,18,19], which is consistent with our study. In some cases, there is a skin rash right after birth, but the rash may also occur several days later after exposure to ultraviolet light, which may cause or aggravate the rash. In a cohort study of 57 infants, rashes can be recognized at an average time of 6 weeks after birth [21]. In our study, the appearance time of rash was 16.5 days after birth in average. None appeared immediately after birth, with the earliest appearance time of 5 days, and latest of 30 days after birth. Other systems involvement can occur with no obvious symptoms, including thrombocytopenia in 1\u0026ndash;22 days after birth, and anemia, neutropenia and liver enzymes elevation within 2\u0026ndash;3 months after birth, which need to pay more attention. Therefore we recommend to monitor closely the hepatic and hematological system within 2\u0026ndash;3 months after birth, and treat the patients if necessary. Similar to our data, a follow-up study of infants who had positive anti-SSA antibodies found that some patients developed NLE during follow-up, whose hematological system was involed as anemia, neutropenia, or thrombocytopenia without symptoms. About 56% of cases showed mild and temporary transaminase elevation in 3 months after birth. So researchers recommend clinical and laboratory examinations at the age of 3 months after birth, because hepatic and hematological systems are most probably affected at this time point [22]. As children grow up, the specific autoantibodies taken from their mothers gradually turn negative, and the NLE symptoms and signs also gradually disappear except for cardiac block [22]. The prognosis is good for children with dermal, hepatic or haematological systems involvement. A follow-up study of infants whose mothers had positive anti-SSA antibodies found that a majority of hematological system involvement recovered completely within 9 months after birth [22]. In our study, the hematological system involvement could recover within 3 months after birth. The hepatic system involvement could all recover within 12 months, and mostly 6 months after birth. But some of the conditions were serious and required timely and active intervention, such as thrombocytopenia. In a severe case, platelet (PLT) could be reduced to 35*109/L due to NLE.\u003c/p\u003e\n\u003cp\u003eResearchers have found that the anti-SSA of 10% of the infants whose mothers have positive anti-SSA are still positive at the age of 9 months [22]. We have found that the median time for anti-SSA, SSB and RNP antibodies to turn negative is 12 months after birth. What\u0026rsquo;s more, the involved systems of NLE patients, especially hepatic system, may not recover until 12 months after birth for some babies. So we recommend that the high-risk babies of NLE to be followed up until at least 12 months after birth.\u003c/p\u003e\n\u003cp\u003eStudies have shown that young mother, first child and lack of glucocorticoid therapy may be risk factors to increase the risk of NLE of the offspring [23]. Other studies believe that the interaction of genetic susceptibility, intrauterine environment and maternal antibodies is more complex than currently known [24]. We have found that there is no significant difference between the NLE group and the non-NLE group in mothers\u0026rsquo; age, delivery mode, abnormal child-bearing history, or the usage of prednisone or hydroxychloroquine during pregnancy, neither of the kinds and amounts of positive autoantibodies, indicating that no single factor can affect the systems involvement of NLE except for cardiac block.\u003c/p\u003e\n\u003cp\u003eThere are some limitations in this study. First of all, our study is a single-center study. Due to the standardized prenatal health care in our center, no neonates have cardiac block in this study. Secondly, this study only includes full-term infants. Thirdly, babies are followed up to 24 months after birth in our study, and more follow-up studies are still needed for the long-term prognosis of high-risk groups of NLE.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the dermal, hepatic, and hematological systems involvement of NLE can gradually appear during follow-up. The affected systems can recover with a good prognosis, but some of the conditions are serious and require timely and active intervention. No single factor has been found to predict whether the high-risk offspring will suffer from NLE or not. Therefore, for all the high-risk populations of NLE, it is necessary to follow up closely within one year after birth, paying attention to the dermal, hepatic, and hematological systems involvement and monitoring their autoantibodies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cem\u003eALP\u003c/em\u003e: Alkaline phosphatase\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eALT\u003c/em\u003e: Alanine aminotransferase\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAST\u003c/em\u003e: Aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCHB\u003c/em\u003e: Congenital heart block\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGGT\u003c/em\u003e: Glutamate transpeptidase\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNLE\u003c/em\u003e: Neonatal lupus erythematosus\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePLT\u003c/em\u003e: Platelet\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRNP\u003c/em\u003e: Ribonucleoprotein\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSLE\u003c/em\u003e: Systemic lupus erythematosus\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSS\u003c/em\u003e: Sjogren\u0026apos;s Syndrome\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSSA\u003c/em\u003e: Sj\u0026ouml;gren\u0026rsquo;s syndrome types A autoantigens\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSSB\u003c/em\u003e: Sj\u0026ouml;gren\u0026rsquo;s syndrome types B autoantigens\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTBA\u003c/em\u003e: Total bile acid\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was funded by Ministry of Science and Technology of the People\u0026apos;s Republic of China, National Key Research and Development Program of China. Grant number: 2021YFC2702004.\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eLi Zhenghong and Song Hongmei initiated and supervised this research. Ma Jingran and Zhang Lejia performed the study. Ma Jingran analyzed the data, wrote the manuscript and prepared the figures.\u003c/p\u003e\n\u003cp\u003eEthics approval\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Institutional Review Board of Peking Union Medical College Hospital.\u003c/p\u003e\n\u003cp\u003eConsent to participate\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003eConsent to publish\u003c/p\u003e\n\u003cp\u003eThe authors affirm that consent to publish has been received from all participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Heelan K, Watson R, Collins SM (2013) Neonatal lupus syndrome associated with ribonucleoprotein antibodies. Pediatr Dermatol 30: 416\u0026ndash;423. https://doi:10.1111/pde.12088\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Savino F, Viola S, Tarasco V, Locatelli E, Ricagni A, Coppo P (2016) Neonatal lupus erythematosus: a cutaneous cases based update. Ital J Pediatr 42:1\u0026ndash;5. https://doi:10.1186/s13052-015-0208-5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Satoh M, Chan EK, Ho LA, et al (2012) Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum 64: 2319\u0026ndash;2327. https://doi:10.1002/art.343800\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Derdulska JM, Rudnicka L, Szykut-Badaczewska A, Mehrholz D, Nowicki RJ, Barańska-Rybak W, Wilkowska A (2021) Neonatal lupus erythematosus \u0026ndash; practical guidelines. J Perinat Med 49:529\u0026ndash;538. https://doi:10.1515/jpm-2020-0543\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Vanoni F, Lava SAG, Fossali EF, Cavalli R, Simonetti GD, Bianchetti MG, Bozzini MA, Agostoni C, Milani GP (2017) Neonatal systemic lupus erythematosus syndrome: a comprehensive review. Clin Rev Allergy Immunol 53:469\u0026ndash;76. https://doi:10.1007/s12016-017-8653-0\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Shao XM, Ye HM, Qiu XS (2018) The appendix. In: Practice of Neonatology, 5th edn. People's Medical Publishing House (PMPH), Beijing, pp 1068\u0026ndash;1081.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e National Health Commission of the People\u0026rsquo;s Republic of China (2021) Reference intervals of clinical biochemistry tests commonly used for children. WS/T 780\u0026ndash;2021. http://www.nhc.gov.cn/fzs/s7852d/202105/3f216b22ed084069b65399f969035358/files/8d4b58cf376d4b129907c19d147b8433.pdf. Accessed 17 May 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Zhuang JW, Liu SZ, Ma L (2018) Neonatal anemia and transfusion. Chinese Journal of Applied Clinical Pediatrics 33: 176\u0026ndash;180. https://doi:10.3760/cma.j.issn.2095-428X.2018.03.005\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e National Health Commission of the People\u0026rsquo;s Republic of China (2021) Reference intervals of blood cell analysis for children. WS/T 779\u0026ndash;2021. http://www.nhc.gov.cn/fzs/s7852d/202105/3f216b22ed084069b65399f969035358/files/b0ae91f953af45db9dd520a0de84b295.pdf. Accessed 17 May 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Klein-Gitelman MS (2016) Neonatal lupus: what we have learned and current approaches to care. Curr Rheumatol Rep 18:60. https://doi:10.1007/s11926-016-0610-z\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Nasef N, Hafez M, Bark A (2014) Neonatal lupus erythematosus. J Neonatol Clin Pediatr 1:002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Buyon JP, Clancy RM (2005) Neonatal lupus: basic research and clinical perspectives. Rheum Dis Clin N Am 31:299\u0026ndash;313. https://doi:10.1016/j.rdc.2005.01.010\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Lee LA (2009) The clinical spectrum of neonatal lupus. Arch Dermatol Res 301:107\u0026ndash;110. https://doi:10.1007/s00403-008-0896-4\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Neiman AR, Lee LA, Weston WL, Buyon JP (2000) Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J Pediatr 137:674. https://doi:10.1067/mpd.2000.109108\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Palit A, Inamadar AC (2012) Current treatment strategies: collagen vascular diseases in children. Indian J Dermatol 57: 449\u0026ndash;458. https://doi:10.4103/0019-5154.103064\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Cimaz R, Spence DL, Hornberger L, Silverman ED (2003) Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr 142:678. https://doi:10.1067/mpd.2003.233\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, et al (2004) Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group. Arthritis Rheum 50:3187. https://doi:10.1002/art.20554\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, Buyon JP; PRIDE Investigators (2008) Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation 117:485. https://doi:10.1161/CIRCULATIONAHA.107.707661\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Barsalou J, Costedoat-Chalumeau N, Berhanu A, et al (2018) Effect of in utero hydroxychloroquine exposure on the development of cutaneous neonatal lupus erythematosus. Ann Rheum Dis 77:1742. https://doi:10.1136/annrheumdis-2018-213718\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Silverman E, Jaeggi E (2010) Non-cardiac manifestations of neonatal lupus erythematosus. Scand J Immunol 72:223. https://doi:10.1111/j.1365-3083.2010.02443.x\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Lee LA (2001) Neonatal lupus: clinical features, therapy, and pathogenesis. Curr Rheumatol Rep 3:391. https://doi:10.1007/s11926-996-0009-3\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Zuppa AA, Riccardi R, Frezza S, Gallini F, Luciano RM, Alighieri G, Romagnoli C, De Carolis S (2017) Neonatal Lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Re 16:427\u0026ndash;432. https://doi:10.1016/j.autrev.2017.02.010\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Luo Y, Zhang L, Fei Y, Li Y, Hao D, Liu Y, Zhao Y (2015) Pregnancy outcome of 126 anti-SSA/Ro-positive patients during the past 24 years\u0026mdash;a retrospective cohort study. Clin Rheumatol 34:1721\u0026ndash;8. https://doi:10.1007/s10067-015-3050-7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Chiou AS, Sun G, Kim J, Wang KC, Marqueling AL (2016) Cutaneous neonatal lupus arising in an infant conceived from an oocyte donation pregnancy. JAMA Dermatol 152:846\u0026ndash;7. https://doi:10.1001/jamadermatol.2016.0001\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Neonatal lupus erythematosus, SSA, SSB, follow up","lastPublishedDoi":"10.21203/rs.3.rs-3176258/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3176258/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e This study aims to analyse the clinical characteristics and risk factors of high-risk groups of neonatal lupus erythematosus (NLE) in term infants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e The high-risk groups of NLE whose mothers were positive of anti-SSA, SSB or U1RNP antibodies during pregnancy were enrolled. They were born from February 2013 to February 2020, with a gestational age not less than 37 weeks. We analyzed their clinical data from birth to 24 months after birth.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total number of 105 cases of NLE high-risk groups were included. Among them, 30 cases were diagnosed with NLE (NLE group) and 75 cases were not (non-NLE group). The affected systems of the NLE group included dermal (13.3%), hepatic (76.0%), and hematological system (43.3%). Hepatic involvement, anemia and thrombocytopenia could not emerge until 60 days, 41 days and 22 days after birth in some cases. The systems involvement could be cured within 3 to 12 months after birth. The clearance time of specific autoantibodies was 12 months after birth. There was no significant difference in clinical characteristics of babies and their mothers between the two groups, neither of the positive rate or clearance time of specific autoantibodies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e After standardized prenatal health care, there is still a high risk of dermal, hepatic, or hematological system involvement for high-risk groups of NLE. There are no specific indicators to predict whether the babies will develop to NLE or not. All of them need to be followed up closely within one year after birth.\u003c/p\u003e","manuscriptTitle":"High-risk groups of Neonatal Lupus Erythematosus in term infants: a birth cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-07-24 05:27:13","doi":"10.21203/rs.3.rs-3176258/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-09-15T10:02:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-09-07T17:34:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30f17be1-5ed1-458e-9f31-8a2eae41ef0b","date":"2023-08-28T14:53:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-19T16:25:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-07-18T23:34:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-07-18T23:25:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2023-07-17T02:53:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"94c19214-4b18-4b70-95f0-7d61fd23a747","owner":[],"postedDate":"July 24th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-23T15:03:09+00:00","versionOfRecord":{"articleIdentity":"rs-3176258","link":"https://doi.org/10.1007/s00431-023-05283-8","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2023-10-17 15:01:00","publishedOnDateReadable":"October 17th, 2023"},"versionCreatedAt":"2023-07-24 05:27:13","video":"","vorDoi":"10.1007/s00431-023-05283-8","vorDoiUrl":"https://doi.org/10.1007/s00431-023-05283-8","workflowStages":[]},"version":"v1","identity":"rs-3176258","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3176258","identity":"rs-3176258","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}