J Clin Immunol (2014) 34:853–863 DOI 10.1007/s10875-014-0069-5 ORIGINAL RESEARCH IgA Deficiency, Autoimmunity & Pregnancy: A Population-Based Matched Cohort Study Jonas F Ludvigsson & Martin Neovius & Olof Stephansson & Lennart Hammarström Received: 1 March 2014 /Accepted: 6 June 2014 /Published online: 9 July 2014 # Springer Science+Business Media New York 2014 Abstract (mean±SD: 278±13 vs 280±14 days, P=0.001). No differ- Background Several autoimmune disorders have been linked ence in preterm birth (<37 weeks) could be detected in deliv- to adverse pregnancy outcome. IgA deficiency shares many eries to women with IgA deficiency vs control deliveries autoimmune traits, but its association with pregnancy out- (5.8 % vs 5.2 %; odds ratio (OR)=1.13, 95%CI=0.85– come is unknown. 1.49), but small for gestational age birth was more common Methods Prospective population-based cohort study in Swe- (4.3 % vs 2.8 %; OR=1.48, 95%CI=1.04–2.10). Women with den of 613 mothers with IgA deficiency (IgA levels<.07 g/L) IgA deficiency also delivered more often by caesarean section diagnosed in 1980–2010 in six university hospitals. In 1973– (16.9 % vs 11.9 %; OR=1.51, 95%CI=1.26–1.82), while no 2010, these women delivered 1,172 singleton infants regis- difference was observed regarding low Apgar score (<7 at tered in the Swedish Medical Birth Register. Each delivery to 5 min; 1.1 % vs 1.0 %; OR=1.18; 95%CI=0.62–2.27). When a woman with IgA deficiency was matched on maternal age, excluding women with autoimmune diseases, the excess risks parity, early pregnancy smoking status, education level, and of adverse pregnancy outcome diminished. delivery year with up to 5 control births (n=5,758). Conclusion There is a small excess risk of certain adverse Results Offspring to women with IgA deficiency had 79 g delivery and perinatal outcomes among offspring to women lower birth weight than controls (mean±SD: 3,457±559 vs with IgA deficiency. These excess risks are attenuated when 3,537±553 g, P<0.001), and 1.4 days shorter gestational age considering the presence of autoimmune diseases. Electronic supplementary material The online version of this article Keywords Autoimmune . childbirth . IgA deficiency . (doi:10.1007/s10875-014-0069-5) contains supplementary material, immunoglobulin . pregnancy . perinatal outcomes which is available to authorized users. J. F. Ludvigsson Department of Medical Epidemiology and Biostatistics, Karolinska Introduction Institutet, Box 281, 171 77 Stockholm, Sweden J. F. Ludvigsson (*) Selective IgA deficiency is an immunodeficiency that is char- Department of Paediatrics, Örebro University Hospital, Örebro acterized by total IgA levels <0.07 g/L,[1] which occurs in University, Örebro, Sweden about 1:200–600 Caucasians. IgA is instrumental for the e-mail: [email protected] mucosal immune defense, and has been linked to recurrent : M. Neovius O. Stephansson respiratory and gastrointestinal infections [2–4]. In addition to Clinical Epidemiology Unit, Department of Medicine, Karolinska an excess risk of infections, individuals with IgA deficiency Institutet, Stockholm, Sweden seem to be at increased risk of death [5] and autoimmunity [6]. O. Stephansson According to WHO estimates, one in ten newborns is Department of Women’s and Children’s Health, Karolinska Institutet, born preterm (<37 completed gestational weeks) [7], Stockholm, Sweden and more than 1 million children die from preterm birth complications each year. Besides an increased neonatal L. Hammarström Department of Laboratory Medicine, Karolinska Institutet, Solna, mortality [8], preterm birth and especially very preterm Sweden birth (<33 completed gestational weeks) has been linked 854 J Clin Immunol (2014) 34:853–863 to cognitive dysfunction (e.g. poor attention, and exec- Covariates utive functions) [9, 8]. Other adverse pregnancy out- comes include low birth weight and intrauterine growth We retrieved data on maternal age, parity, maternal retardation. Both preterm birth and poor intrauterine country of birth, early pregnancy smoking status (data growth are inversely related to full-scale IQ, and skills available from 1982), body mass index (BMI; data in reading, spelling, and math [10]. Also the risk of available from 1992), and delivery year from the Med- bronchopulmonary dysplasia, intraventricular haemor- ical Birth Register. At the first antenatal visit, smoking rhage, retinopathy of prematurity, and poor growth later habits were registered, based on self-reported cigarette in childhood are influenced [11, 12, 8] by preterm birth consumption (non-smoker, 1–10, >11 cigarettes per and birth weight. Finally, preterm birth and low birth day). Maternal education level was retrieved from the weightareatraumaforthewholefamilyandcanhave Education Register at Statistics Sweden and classified as negative psychosocial effects [13]. ≤9, 10–12, and >13 years. Country of birth of the Several autoimmune disorders have been linked to an mother was categorized into Nordic and non-Nordic, increased risk of adverse pregnancy outcome [14–18]. with Sweden, Denmark, Norway, Finland, and Iceland These include celiac disease [19], which often consti- being the Nordic countries. tutes the reason for measuring total IgA subsequently leading up to an IgA deficiency diagnosis. Furthermore, IgA Deficiency Cohort because of the susceptibility for infectious disease among women with IgA-deficiency, this immunodefi- Women with IgA deficiency were identified from laboratory ciency may be linked to an increased risk of premature data from 1980 through 2010 at six university hospitals in contractions and premature rupture of the membranes Sweden (Karolinska Hospital in Stockholm, Sahlgrenska hos- (PROM) leading to preterm birth. However, we are not pital in Gothenburg, the University hospital in Lund, the aware of any study examining IgA deficiency in the University hospital in Linköping, the University hospital in pregnant mother and pregnancy outcome. Umeå and the Academic hospital in Uppsala). These univer- This study aimed to quantify the risk of adverse pregnancy sity hospitals cater for both urban and rural areas. outcome in a population-based cohort of mothers with con- We defined IgA deficiency as having an IgA value firmed IgA deficiency. <0.07 g/L, with normal IgM and IgG levels, in individ- uals ≥4 years of age in accordance with the recommen- dations of the International Union of Immunological Societies Expert Committee on Primary Methods Immunodeficiencies.[23] In the current study we re- quired that all study participants had a low IgA value Setting (below or equal to 0.07 g/L) recorded after the age of 10 years. Only if levels are persistently low after the In Sweden, antenatal and delivery care is provided for free, age of 10 years can IgA deficiency be diagnosed accu- with a participation rate in the antenatal care program close to rately since younger children may still have transiently 100 %. The first visit commonly takes place at the end of the low IgA values between 4 and 10 years of age.[24]In first trimester [20]. Sweden, most laboratories use nephelometry to measure total IgA levels. In this study we regarded pregnancies Register Linkage to women who at some stage after 10 years of age had IgA deficiency as exposed (both those with diagnosed The Swedish Medical Birth Register includes information on IgA deficiency before pregnancy and those diagnosed >98 % of all births in Sweden since 1973. Starting at the first after pregnancy, since almost all IgA deficiency is prev- antenatal visit, information is prospectively collected, using alent since childhood even if diagnosed later). standardized pregnancy, delivery and infancy records.[21] Women with IgA deficiency were then linked to the Swed- Data from the Medical Birth Register were linked to a ish Medical Birth Register to identify those who had delivered clinical database of patients with diagnosed IgA deficiency. singleton infants between 1973 and 2010. Thereafter the analyses were performed on the delivery level, as the same woman could contribute more than one delivery Control Births during the study period. We excluded multiple births since they differ in duration of gestation and fetal growth, as well as Five control births per delivering woman with IgA deficiency having a higher occurrence of pregnancy and perinatal com- were sampled from the Swedish Medical Birth Register plications [22]. matched on maternal age (±1 year), early pregnancy smoking J Clin Immunol (2014) 34:853–863 855 status (non-smoker/1–10/≥11 cigarettes per day/missing), ed- diagnosis for IgA deficiency. In sub-analyses, we looked ucation level (≤9/10–12/≥13 years/missing), parity (nullipa- at pregnancy outcome in women with IgA deficiency rous/parous), country of birth (Nordic/non-Nordic), and de- diagnosis recorded before delivery, in women with BMI livery year (±1 year). If a full five matched control births could recorded (adjusting for BMI in the logistic regressions), not be found, the IgA patients and their controls were still and in women without an autoimmune disease diagnosis included. If no matched control births could be identified, the prior to delivery (using the secondary matched control IgA patients were excluded (n=8). group). For relevant diagnostic codes see Table VII. Presence of autoimmune diseases, including rheuma- Data were analyzed using SAS (version 9.4). Reported P- toid arthritis, juvenile idiopathic arthritis, inflammatory values are two-sided and P-values <0.05 were considered bowel disease, celiac disease, systemic lupus erythema- statistically significant. tosus, myasthenia gravis, hypothyroidism, hyperthyroid- ism, and type 1 diabetes, was determined via visits in inpatient (1968–2010) and nonprimary outpatient care (2001–2010) based on the first main diagnosis listing Results for any of the diseases. A secondary control cohort was also matched using the We identified 1,404 women who had been diagnosed with same matching factors, but requiring both patients with IgA IgA deficiency at any of the participating university hospitals deficiency and controls to be free of autoimmune diseases between 1980 and 2012.