Management and the pregnancy outcomes of patients positive for anti-parietal cell antibody

1. Introduction

Autoantibodies and autoimmune diseases were commonly investigated for possible etiologic factors for obstetric complications, such as miscarriage, intrauterine fetal death, or stillbirth. The heterogenous clinical presentation of these diseases and overlap of the autoantibodies at different disorders make all autoantibodies as a possible risk factor for obstetric complications [9]. Despite the strict relationship of antibodies, such as anticardiolipin, antiphospholipid (aPL), or lupus anticoagulant, with obstetric complications, lot of data have indicated the role of other autoantibodies in pregnancy complications [7, 15, 23].

Anti-parietal cell antibodies (APCAs) are autoantibodies that are strictly related with atrophic gastritis and pernicious anemia [13]. Most of patients with atrophic gastritis were found to have APCA despite lack of complete specificity of these autoantibodies to disease [24]. The main target for APCA is the gastric proton pump, which is the H+/K+ ATPase pump [8]. This pump creates hydroxychloric acid, which is essential for gastric pathophysiology and maintainance of natural gastric flora [25]. APCA antibodies are also found in IgG, IgA, and IgM forms in the circulation [5]. The H+/K+ ATPase proton pumps have also been reported to be expressed in the microvillus membrane of syncytitrophoblasts, which makes these cells a possible target for APCA autoantibodies [12].

APCAs are also related to other autoimmune clinical situations [22]. The most common relationship of these autoantibodies was in thyroid disorders, including Hashimoto or Graves-Basedow disease [26]. APCA positivity was found in patients with Graves disease and Hashimoto thyroiditis at 55.9% and 44.0%, respectively [27, 28].

Methylentetrahydrofolate reductase (MTHFR) polymorphisms and inherited/acquired thrombophilias are also related with poor obstetric outcomes based on many studies [10, 21, 29].

In this study, we retrospectively evaluated the pregnancy outcomes of patients positive for APCA. Coexisting risk factors, such as MTHFR polymorphisms, positivity for other autoimmune antibodies or thrombophilias, were also evaluated in terms of obstetric outcomes.

2. Material and methods

This is a retrospective study that evaluated the pregnancy outcomes of 39 patients with detected APCA positivity within one year before their pregnancy (and positive at the begining of their pregnancies). The required data were obtained from Hacettepe University Division of Perinatology registries and electronical database of the institution from 2012 to 2017. Due to institution characteristics and our division’s status as a referral center for patients with poor obstetric histories, most patients had prior pregnancy losses or history of congenital malformations. After investigation of all possible etiologic factors, the patients were included in a special antenatal care program within the framework of perinatology. The patients were administered with low-dose low-molecular-weight heparin (LMWH) (enoxaparine, 1 × 2000 Anti-XA IU/ 0.2 mL/day), and low-dose corticosteroid (methylprednisolone, 1 × 4 mg/day orally) and low-dose salysilic acid (coraspirin, 100 mg/day).

The antibodies had been studied because of suspicion of any autoimmune disease related with the patients’ clinical status or for the etiological investigation of prior obstetric complications and pregnancy losses prior to pregnancies. The other antibodies studied included anti-nuclear antibody (ANA), extractable nuclear antigen (ENA), anti-double-stranded DNA (anti-dsDNA), anti-smooth muscle (ASMA), anti-mitochondrial (AMA), anti-thyroid peroxidase (antiTPO), anti-thyroglobulin (anti-TG), and anti- phospholipid (aPL) in accordance with patients’ clinical status. For the laboratory analysis, 5 ml of intravenous blood sample, irrespective of fasting status, was obtained from each study subject in plain tubes, and the serum was separated. All the samples were stored at - 20 ∘ C. ANA, APCA, ASMA, and AMA levels were measured with indirect immunofluorescence method (Euroimmun ® , Lübeck, Germany) in the biochemistry laboratory. The enzyme-linked immunosorbent assay was used to determine the concentration of anti-dsDNA and aPL antibodies following the manufacturer instructions (Euroimmun ® , Lübeck, Germany). Anti-TPO levels were determined by using Radioimmunoassay (Thermo Scientific BRAHMS ® , Annapolis, MD, USA), and anti-TG antibody levels were determined by using the chemiluminescence method (Immulite ® 2000, DPC, Tarrytown, NY, USA). A titer of 1/40 for ANA, ASMA, and AMA was accepted as a positive result. Levels of 40 IU/mL, 80 IU/mL, 1.1 IU/mL, and 12 MPLU/mL were considered positive for anti-TG, anti-TPO, anti-dsDNA, and anti-phospholipid antibodies IgG/M, respectively.

Patients with any detected autoimmune disease were excluded to prevent any bias related to autoimmune disease. Patients who were followed up in different institutions were also excluded from the study. The pregnancy outcomes of the patients were evaluated. After exclusion of “early pregnancy miscarriages,” the patients were evaluated in terms of gestational week at birth, birth-weight, APGAR scores, and admissions to neonatal intensive care unit (NICU). The patients were also classified based on the existance of any other antibodies, MTHFR polymorphisms, and any diagnosed thrombophilias. Further analysis was performed between these groups, and pregnancy outcomes were evaluated in terms of APCA titers with a threshold of 1/40. We also used the Beksac Obstetrics Index (BOI), which is an obstetrics index for the assessment of risk levels of the high-risk pregnancy groups [(number of alive children + π /10)/Gravida] ( π = 3.14) to compare these groups for the evaluation of their previous obstetric histories [4].

The data were evaluated using descriptive statistics and Mann-Whitney U test. A p value 0.05 was considered significant. All statistical calculations were performed using Statistical Package for Social Sciences (SPSS) for Windows (SPSS version 23; SPSS Inc., Chicago, IL, USA) software package.

This retrospective study was approved by Hacettepe University Ethics Committee (number: GO 18/326).

3. Results

In this study, we have shown the demographic characteristics, personal characteristics, and pregnancy outcomes of patients positive for APCA (Table 1). Of 39 pregnancies, three resulted in abortions at the ninth, tenth, and twentieth gestational weeks, respectively (7.6%). Two of these patients had APCA titers $>$ 1/40, and the other patients had an APCA titer 1/40. The median gestational week at birth was 37, with a median birthweight of 2795 g. The median APGAR scores were 8, 9, and 9 for the first, fifth, and tenth minute, respectively. Of 36 fetuses, nine (25%) were admitted to the NICU for different indications. Further analysis was performed to demonstrate the effect of increasing APCA titers or additional risk factors, such as MTHFR polymorphisms, positivity for other autoantibodies or coexisting thrombophilias (Table 2). Analysis included gestational week at birth, birth weight, APGAR scores at the first, fifth, and tenth minute and NICU admission. No significant difference was observed for the analyses within the groups, evaluating APCA titers (greater or lesser than 1/40), MTHFR polymorphisms, or additional thrombophilia status. The only significant difference was observed for the fifth minute APGAR scores between the groups 2 with positivity for other autoantibodies ( p = 0.036). The difference was in favor of the group with only one antibody-positivity based on the interquartile ranges and mean values. Despite lack of significant differences, patients with more than one autoimmune antibody positivity had lower APGAR scores for the first and tenth minute ( p = 0.727; p = 0.083). Further evaluation also showed a lower median birthweights in the group with positivity for multiple antibodies (2770 g [2200–3570] vs 2930 g [2100–3970]; p = 0.391). Gestational week at birth was also found to have a lower median in the group with positivity for multiple antibodies (36 [34–37] vs 37 [35–38]; p = 0.658). BOI analysis showed a statistically significant difference between the groups, demonstrating that having more than one “antibody positivity” had a worse obstetric history compared with having positivity for only APCA as an autoimmune antibody (0.104 [0.039–0.657] vs 0.314 [0.063–0.771]; p = 0.028).

The clinical effect of autoimmunity (autoimmune diseases and autoantibodies) is well studied for many years [6]. aPL, lupus anticoagulant, or anti-beta-2 glycoprotein-1 was known to be related with recurrent misscarriages and obstetric complications [18]. Autoimmune diseases, such as systemic lupus erythematosus, Hashimoto thyroiditis, Behçet disease, or Celiac disease, were also related with adverse pregnancy outcomes [2, 14, 16, 19]. Despite each disease’s spesific clinical features, placental inflammation as a result of autoimmunity may be the reason for adverse pregnancy outcomes. Inflammatory processes at the maternal-fetal interface (injury of intervillous space structures; endothelial cells in spiral veins, syncytiotrophoblasts covering the chorionic villi, superficial and glandular epithelial cells in the decidua, endovascular trophoblasts) may be the reasons for adverse results concerning both early and late pregnancy complications. Due to these facts, each autoimmune process may be investigated in terms of pregnancy complications. To the best of our knowledge, this is the first study focusing on pregnancy outcomes of patients with APCA positivity. Investigation of APCA is also important in our country because of the high prevelance (1.85%) in the Turkish population [1].

We have demonstrated that positivity for more than one autoantibody, including APCA, seems to be related to lower APGAR scores. We have also demonstrated statistical significance only at the fifth minute scores, but the first and tenth minute scores were found to be better in the group with only one autoantibody positivity ( p = 0.727; p = 0.083). Gestational week and birthweights were higher in the group with just one autoantibody positivity despite lack of any statistical significance. We have shown statistically significantly better BOI in “only APCA positive” group compared with “multiple antibody positive” group ( p = 0.028). Mumusoglu et al. reported that rate of recurrent pregnancy loss tends to be higher with increased number of autoantibodies [17]. Similar results acquired from different studies may suggest that increased immunological inflammation and vascular damage at the maternal-fetal interface might be increasing obstetric complications. This fact is also supported by the studies revealing improved pregnancy outcomes by anti-inflammatory therapies, such as low-dose low-molecular-weight heparin [3, 11, 20].

In other analyses regarding MTHFR polymorhpisms, inherited/acquired thrombophilias or APCA titers showed no statistically significant difference. Statistical insignificance may be explained by the relatively low number of cases. Similar results between groups may also be explained by the fact that patients were under a special treatment protocol regarding their clinical status and obstetric histories.

To the best of our knowledge, this is the first study focusing on pregnancy outcomes of patients positive for APCA, and this is the most important strength of our study. We also excluded patients with known autoimmune diseases to avoid any bias related to autoimmune disease-related pregnancy complications. Despite these strengths, the low number of cases and retrospective design of the study are the limitations of this study. Our results must also be evaluated by considering all patients being administered with an anti-inflammatory treatment regimen.

In conclusion, patients with APCA positivity must also be carefully evaluated similar to those with positivities for other autoantibodies. Patients with more than one autoantibody positivity, including that for APCA, must be considered as high-risk patients. Further investigations are needed to improve our understanding in this field.