Original Article
Arthritis Care & Research DOI 10.1002/acr.22373
Original article SLE and outcomes in first and subsequent births based on data from a national birth registry Marianne Wallenius1,2, Kjell Å. Salvesen3,4, Anne K. Daltveit5,6, Johan F. Skomsvoll1,2 1
National Service for Pregnancy and Rheumatic Diseases, Dept. of Rheumatology, Trondheim University Hospital, Trondheim, Norway. 2Dept. of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. 3Dept. of Obstetrics and Gynecology, Clinical Sciences, Lund University, Lund, Sweden. 4Dept. of Laboratory Medicine. Women’s and Child Health, Norwegian University of Science and Technology, Trondheim, Norway. 5 Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. 6Medical Birth Registry of Norway, Division of Epidemiology, Norwegian Institute of Public Health, Bergen, Norway Address of corresponding author: Marianne Wallenius National Service for Pregnancy and Rheumatic Diseases, Dept. of Rheumatology, St Olav’s Hospital, Bevegelsessenteret, N-7006 Trondheim E-mail: [email protected] Fax number: +4773598795 Telephone number: +4772826417
Key words: pregnancy, SLE, birth order, national registry, birth outcome, inflammatory rheumatic disease Word count abstract: 250 Word count article (not including appendix, tables and references): 3040
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/acr.22373 © 2014 American College of Rheumatology Received: Jun 10, 2013; Revised: Apr 30, 2014; Accepted: May 13, 2014
Arthritis Care & Research
SLE, birth order and pregnancy outcome Disclosure statement: The authors have declared no conflicts of interest
Funding: This work was supported by the Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology
2 John Wiley & Sons, Inc.
Page 2 of 25
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Arthritis Care & Research
SLE, birth order and pregnancy outcome
Abstract Objective: To examine associations between systemic lupus erythematosus (SLE) and outcomes in first and subsequent births. Methods: Data from the Medical Birth Registry of Norway in the period 1.12.1998 to 31.12 2009 were used to assess maternal and perinatal outcomes in women diagnosed with SLE compared with the general population. Outcomes of first and subsequent births were analyzed separately. Associations between SLE and pregnancy outcomes were assessed in logistic regression analyses and presented as adjusted odds ratio (aOR) after adjustments for maternal age, gestational age, smoking habits and previous cesarean section when relevant. Results: We analyzed 95 first and 145 subsequent births in patients and compared with references. The risk of cesarean section (CS) was twofold higher in SLE patients in first and subsequent births. More newborns of patients had birth weight less than 2500 grams, aOR 5.00 (95 % confidence interval (CI) (3.02, 8.27)) in first birth and aOR 4.33 (2.64, 7.10) in subsequent births. Also, preterm birth was more frequent among SLE patients, aOR 4.04 (2.45, 6.56) in first birth and aOR 3.13 (1.97, 4.98) in subsequent births. Congenital malformations were more prevalent among children of patients than references, aOR 2.71 (1.25, 5.86) in first birth and aOR 3.13 (1.69, 5.79) in subsequent births. Perinatal death was more frequent in first births among patients, aOR 7.34 (2.69, 20.03), but no difference was observed in subsequent births.
3 John Wiley & Sons, Inc.
Arthritis Care & Research
SLE, birth order and pregnancy outcome Conclusion: Pregnancy complications were more frequent in SLE patients than references, and the greatest differences between groups were observed in first births.
Bullet points SLE is associated with pregnancy complications. In general, the greatest differences between patients and references were associated with the first birth.
4 John Wiley & Sons, Inc.
Page 4 of 25
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Arthritis Care & Research
SLE, birth order and pregnancy outcome
Systemic lupus erythematosus (SLE) often presents in women of childbearing age. Up to 70 % of SLE women have signs of disease activity in pregnancy, and most common is skin rash or symptoms from the joints (1, 2). During pregnancy up to 50 % of the patients may experience worsening of the disease activity (3). Previous studies have shown increased risks of several problems in SLE women compared to healthy controls. Hematological and renal complications of the patients are frequently reported as well as hypertension and preeclampsia (4, 5). Prematurity, intrauterine growth restriction, low birth weight and neonatal lupus are the most frequently reported complications for the newborn (4, 5). Fetal loss is also of major concern in SLE pregnancies (5-8). Few studies have examined SLE associated congenital malformations (9-11). In general, pregnancy complications are more frequently observed in the first pregnancy, e.g. low birth weight and operative deliveries (12-14). The risk of cesarean section (CS) in nulliparous women with spontaneous start of labor, cephalic presentation and no previous scar has been reported to be 2.5 times higher than for comparable parous women (15). The reason why nulliparous women carry higher risks is not fully understood although it has been known for more than 40 years (16, 17). Separate analyses of outcomes in first and subsequent births for pregnant women with SLE have not been previously published. The purpose of this study was to examine pregnancy outcomes in first and subsequent births among women with SLE versus references from the general
5 John Wiley & Sons, Inc.
Arthritis Care & Research
SLE, birth order and pregnancy outcome population with main focus on small for gestational age, preterm birth, perinatal death and major congenital malformations.
Material and Methods Setting The Medical Birth Registry of Norway (MBRN) comprising more than 2.4 million births in 1967-2009 is operated at the University of Bergen and organized under the Norwegian Institute of Public Health (18, 19). MBRN used the same notification form 1967-1998. This form comprised data on all live births as well as stillbirths after 16 weeks of gestation. A more detailed form was introduced December 1st 1998, that comprises data on all births (spontaneous abortions, live births and stillbirths) after 12 weeks of gestation (19). Data on complications, maternal disease and mode of delivery were entered into the notification form as free text until 1998 and in checkboxes or as free text from December 1st 1998 onwards. The attending midwife is responsible for the completion of the notification form at the end of each birth, and the form is co-signed by the attending physician. The notification form is received at MBRN within one week after delivery. Complete ascertainment of the births is ensured through a record linkage with the National Population Registry run by Statistics Norway. The birth notification form includes data on the mother’s health at birth, before and during pregnancy and characteristics of the newborn within the first week after delivery. Among maternal pre-pregnant chronic diseases also renal disease is included, and the diseases are notified in specific checkboxes (yes / no) or coded according to the International Classification of Diseases, 10th edition (ICD-10). The 6 John Wiley & Sons, Inc.
Page 6 of 25
Page 7 of 25
Arthritis Care & Research
SLE, birth order and pregnancy outcome information in the form is based on three elements: 1) a standardized, national form used during pregnancy by the patient’s physician, 2) oral information from the patient when admitted to the hospital and 3) information from the doctor and the midwife about the actual delivery and the newborn. The form is also updated at MBRN with further information on neonatal conditions. Congenital malformations include severe (major) malformations diagnosed during the neonatal period or during pediatric follow-up within the first year. Data from the MBRN are also routinely linked to the Cause of Death Registry by the national, unique identification number to obtain information on infant mortality. After December 1st 1998 women diagnosed with SLE were registered by specific coding according to the ICD-10 classification system. The diagnosis is based on information from the patient’s physician and information in the patient records at the hospital. In the current study we have used data from women diagnosed with SLE giving birth in the period December 1st 1998 to December 31st 2009. The study was carried out in compliance with the Helsinki Declaration and was approved by the Regional Ethics Committee of Central Norway (REK diary number 2011/127-3) Exposure Anonymized births were stratified into first birth and subsequent births. First birth was defined as the first delivery of a nulliparous woman without any previous spontaneous abortions, live birth or stillbirth from gestational week 12 onwards registered in MBRN. Women diagnosed with SLE in the MBRN registry (ICD-10 codes M32.1, M32.8, M32.9) formed the patient group. Reference deliveries were 7 John Wiley & Sons, Inc.
Arthritis Care & Research
SLE, birth order and pregnancy outcome all other deliveries in women not registered with any inflammatory rheumatic disease during the study period. Births in women diagnosed with inflammatory joint diseases, inflammatory connective tissue diseases or inflammatory vasculitic diseases (3200 births) were excluded from the study (Appendix). Outcomes Variables in MBRN have been defined after consensus among obstetricians, neonatologists and epidemiologists. Data on maternal characteristics, parity, assisted reproduction (all methods combined), maternal renal disease before pregnancy and pregnancy complications (i.e. preeclampsia)(20, 21), hypertension, acute thrombosis, induction of labor (amniotomy, oxytocin, prostaglandin), preterm delivery (24 hours, mechanical disproportion or uterine dysfunction / atony) and cesarean section (CS) ( total, elective, acute) were retrieved from MBRN . MBRN also provided data on placental weight (PW) and data on the newborn (gender, birth weight (BW)) and transfer to the neonatal intensive care unit (NICU). Apgar scores after 1 or 5 minutes
Arthritis Care & Research DOI 10.1002/acr.22373
Original article SLE and outcomes in first and subsequent births based on data from a national birth registry Marianne Wallenius1,2, Kjell Å. Salvesen3,4, Anne K. Daltveit5,6, Johan F. Skomsvoll1,2 1
National Service for Pregnancy and Rheumatic Diseases, Dept. of Rheumatology, Trondheim University Hospital, Trondheim, Norway. 2Dept. of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. 3Dept. of Obstetrics and Gynecology, Clinical Sciences, Lund University, Lund, Sweden. 4Dept. of Laboratory Medicine. Women’s and Child Health, Norwegian University of Science and Technology, Trondheim, Norway. 5 Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. 6Medical Birth Registry of Norway, Division of Epidemiology, Norwegian Institute of Public Health, Bergen, Norway Address of corresponding author: Marianne Wallenius National Service for Pregnancy and Rheumatic Diseases, Dept. of Rheumatology, St Olav’s Hospital, Bevegelsessenteret, N-7006 Trondheim E-mail: [email protected] Fax number: +4773598795 Telephone number: +4772826417
Key words: pregnancy, SLE, birth order, national registry, birth outcome, inflammatory rheumatic disease Word count abstract: 250 Word count article (not including appendix, tables and references): 3040
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/acr.22373 © 2014 American College of Rheumatology Received: Jun 10, 2013; Revised: Apr 30, 2014; Accepted: May 13, 2014
Arthritis Care & Research
SLE, birth order and pregnancy outcome Disclosure statement: The authors have declared no conflicts of interest
Funding: This work was supported by the Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology
2 John Wiley & Sons, Inc.
Page 2 of 25
Page 3 of 25
Arthritis Care & Research
SLE, birth order and pregnancy outcome
Abstract Objective: To examine associations between systemic lupus erythematosus (SLE) and outcomes in first and subsequent births. Methods: Data from the Medical Birth Registry of Norway in the period 1.12.1998 to 31.12 2009 were used to assess maternal and perinatal outcomes in women diagnosed with SLE compared with the general population. Outcomes of first and subsequent births were analyzed separately. Associations between SLE and pregnancy outcomes were assessed in logistic regression analyses and presented as adjusted odds ratio (aOR) after adjustments for maternal age, gestational age, smoking habits and previous cesarean section when relevant. Results: We analyzed 95 first and 145 subsequent births in patients and compared with references. The risk of cesarean section (CS) was twofold higher in SLE patients in first and subsequent births. More newborns of patients had birth weight less than 2500 grams, aOR 5.00 (95 % confidence interval (CI) (3.02, 8.27)) in first birth and aOR 4.33 (2.64, 7.10) in subsequent births. Also, preterm birth was more frequent among SLE patients, aOR 4.04 (2.45, 6.56) in first birth and aOR 3.13 (1.97, 4.98) in subsequent births. Congenital malformations were more prevalent among children of patients than references, aOR 2.71 (1.25, 5.86) in first birth and aOR 3.13 (1.69, 5.79) in subsequent births. Perinatal death was more frequent in first births among patients, aOR 7.34 (2.69, 20.03), but no difference was observed in subsequent births.
3 John Wiley & Sons, Inc.
Arthritis Care & Research
SLE, birth order and pregnancy outcome Conclusion: Pregnancy complications were more frequent in SLE patients than references, and the greatest differences between groups were observed in first births.
Bullet points SLE is associated with pregnancy complications. In general, the greatest differences between patients and references were associated with the first birth.
4 John Wiley & Sons, Inc.
Page 4 of 25
Page 5 of 25
Arthritis Care & Research
SLE, birth order and pregnancy outcome
Systemic lupus erythematosus (SLE) often presents in women of childbearing age. Up to 70 % of SLE women have signs of disease activity in pregnancy, and most common is skin rash or symptoms from the joints (1, 2). During pregnancy up to 50 % of the patients may experience worsening of the disease activity (3). Previous studies have shown increased risks of several problems in SLE women compared to healthy controls. Hematological and renal complications of the patients are frequently reported as well as hypertension and preeclampsia (4, 5). Prematurity, intrauterine growth restriction, low birth weight and neonatal lupus are the most frequently reported complications for the newborn (4, 5). Fetal loss is also of major concern in SLE pregnancies (5-8). Few studies have examined SLE associated congenital malformations (9-11). In general, pregnancy complications are more frequently observed in the first pregnancy, e.g. low birth weight and operative deliveries (12-14). The risk of cesarean section (CS) in nulliparous women with spontaneous start of labor, cephalic presentation and no previous scar has been reported to be 2.5 times higher than for comparable parous women (15). The reason why nulliparous women carry higher risks is not fully understood although it has been known for more than 40 years (16, 17). Separate analyses of outcomes in first and subsequent births for pregnant women with SLE have not been previously published. The purpose of this study was to examine pregnancy outcomes in first and subsequent births among women with SLE versus references from the general
5 John Wiley & Sons, Inc.
Arthritis Care & Research
SLE, birth order and pregnancy outcome population with main focus on small for gestational age, preterm birth, perinatal death and major congenital malformations.
Material and Methods Setting The Medical Birth Registry of Norway (MBRN) comprising more than 2.4 million births in 1967-2009 is operated at the University of Bergen and organized under the Norwegian Institute of Public Health (18, 19). MBRN used the same notification form 1967-1998. This form comprised data on all live births as well as stillbirths after 16 weeks of gestation. A more detailed form was introduced December 1st 1998, that comprises data on all births (spontaneous abortions, live births and stillbirths) after 12 weeks of gestation (19). Data on complications, maternal disease and mode of delivery were entered into the notification form as free text until 1998 and in checkboxes or as free text from December 1st 1998 onwards. The attending midwife is responsible for the completion of the notification form at the end of each birth, and the form is co-signed by the attending physician. The notification form is received at MBRN within one week after delivery. Complete ascertainment of the births is ensured through a record linkage with the National Population Registry run by Statistics Norway. The birth notification form includes data on the mother’s health at birth, before and during pregnancy and characteristics of the newborn within the first week after delivery. Among maternal pre-pregnant chronic diseases also renal disease is included, and the diseases are notified in specific checkboxes (yes / no) or coded according to the International Classification of Diseases, 10th edition (ICD-10). The 6 John Wiley & Sons, Inc.
Page 6 of 25
Page 7 of 25
Arthritis Care & Research
SLE, birth order and pregnancy outcome information in the form is based on three elements: 1) a standardized, national form used during pregnancy by the patient’s physician, 2) oral information from the patient when admitted to the hospital and 3) information from the doctor and the midwife about the actual delivery and the newborn. The form is also updated at MBRN with further information on neonatal conditions. Congenital malformations include severe (major) malformations diagnosed during the neonatal period or during pediatric follow-up within the first year. Data from the MBRN are also routinely linked to the Cause of Death Registry by the national, unique identification number to obtain information on infant mortality. After December 1st 1998 women diagnosed with SLE were registered by specific coding according to the ICD-10 classification system. The diagnosis is based on information from the patient’s physician and information in the patient records at the hospital. In the current study we have used data from women diagnosed with SLE giving birth in the period December 1st 1998 to December 31st 2009. The study was carried out in compliance with the Helsinki Declaration and was approved by the Regional Ethics Committee of Central Norway (REK diary number 2011/127-3) Exposure Anonymized births were stratified into first birth and subsequent births. First birth was defined as the first delivery of a nulliparous woman without any previous spontaneous abortions, live birth or stillbirth from gestational week 12 onwards registered in MBRN. Women diagnosed with SLE in the MBRN registry (ICD-10 codes M32.1, M32.8, M32.9) formed the patient group. Reference deliveries were 7 John Wiley & Sons, Inc.
Arthritis Care & Research
SLE, birth order and pregnancy outcome all other deliveries in women not registered with any inflammatory rheumatic disease during the study period. Births in women diagnosed with inflammatory joint diseases, inflammatory connective tissue diseases or inflammatory vasculitic diseases (3200 births) were excluded from the study (Appendix). Outcomes Variables in MBRN have been defined after consensus among obstetricians, neonatologists and epidemiologists. Data on maternal characteristics, parity, assisted reproduction (all methods combined), maternal renal disease before pregnancy and pregnancy complications (i.e. preeclampsia)(20, 21), hypertension, acute thrombosis, induction of labor (amniotomy, oxytocin, prostaglandin), preterm delivery (24 hours, mechanical disproportion or uterine dysfunction / atony) and cesarean section (CS) ( total, elective, acute) were retrieved from MBRN . MBRN also provided data on placental weight (PW) and data on the newborn (gender, birth weight (BW)) and transfer to the neonatal intensive care unit (NICU). Apgar scores after 1 or 5 minutes
