the impact of primary sjogren's syndrome on pregnancy outcome: our series and review of the...
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Autoimmunity Reviews 13 (2014) 103–107
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Review
The impact of primary Sjogren's syndrome on pregnancy outcome:Our series and review of the literature
Sara De Carolis a,⁎, Silvia Salvi a, Angela Botta a, Serafina Garofalo a, Cristina Garufi b,Sergio Ferrazzani a, Maria Pia De Carolis a
a Department of Obstetrics, Gynaecology, and Pediatrics, Catholic University of Sacred Heart, Rome, Italyb Department of Rheumatology, Sapienza Rome University, Italy
⁎ Corresponding author at: Department of ObstetriUniversity, L.go Agostino Gemelli, 8, 00168 Rome, Italy. Te063050160.
E-mail addresses: [email protected], saradec
1568-9972/$ – see front matter © 2013 Elsevier B.V. All rihttp://dx.doi.org/10.1016/j.autrev.2013.09.003
a b s t r a c t
a r t i c l e i n f oArticle history:
Received 1 August 2013Accepted 1 September 2013Available online 14 September 2013Keywords:Autoimmune diseasePregnancyPerinatal outcomeSjogren's syndrome
Objective: Firstly, to investigate the pregnancy outcome of women with primary Sjogren's Syndrome (pSS) in acase–control study; secondly, to perform a review of the literature in order to clarify if the pregnancy outcomeis affected by pSS and influenced by the disease clinical onset.Method of study: Thirty-four pregnancies with pSS and 136 controls were retrospectively collected.Results: Six pregnancies occurred before the pSS diagnosis and 28 after the pSS diagnosis. Two cases were com-plicated by intrauterine atrio-ventricular block. A statistically significant increase of the rate of spontaneousabortions, preterm deliveries and cesarean section was found in pSS pregnancies. The mean neonatal birthweight and the mean neonatal birth weight percentile were significantly lower in the offspring of womenwith pSS in comparison to controls. Similar pregnancy outcome was observed in women with pSS diagnosis
before and after the index pregnancy.Conclusions: Women with pSS experienced complicated pregnancies more frequently than controls, regardless ofthe onset of the symptoms, showing that the immunological disturbance is present throughout the reproductive life.© 2013 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
3.1. Demographic data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043.2. Pregnancy outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
1. Introduction
Sjogren's syndrome is a chronic autoimmune inflammatory diseasethat can present either alone, primary Sjogren's syndrome (pSS), or inthe context of an underlying connective tissue disease, most commonlyrheumatoid arthritis, or systemic lupus erythematosus (secondarySjogren's syndrome) [1]. It is one of the most common autoimmune
cs and Gynaecology, Catholicl.: +39 0630156774; fax: +39
[email protected] (S. De Carolis).
ghts reserved.
diseases with a 0.1–4.8% prevalence rate in the total female population;itmay occur at any age, but it affectsmainlywomenat the fourth decadeof life; the female:male ratio is estimated equal to 9:1 [2]. These dataand the first pregnancy advanced age of the last years explain the in-creased frequency rate of pregnancies in women with pSS.
The hallmark of fetal outcome in SS is the congenital heart block(CHB). It is the most severe complication that may affect the offspringof women with SS and it is attributed to anti-Ro/SSA and/or anti-La/SSB-mediated damage of the atrio-ventricular node. The occurrencerate of CHB has been estimated at approximately 2% in all infants bornto women with anti-Ro/SSA antibodies [3–7] and 3% in all infants bornto women with anti-La/SSB [8–10]. The recurrence rate in a mother
104 S. De Carolis et al. / Autoimmunity Reviews 13 (2014) 103–107
with antibodies, who has a previous child affected, is approximately16–18% [3,8,11]: it is nearly nine times higher than the risk for CHB ina primigravida with the candidate antibodies. About the sex ratio ofCHB, the feminine predisposition for CHB is not clearly established.According to the studies, the proportion of girls among children havingCHB is variable from 83% [12] to 50% [13] in a larger sample.Autoantibody-associated CHB carries a substantial morbidity and mor-tality. The majority of surviving affected children requires permanentpacing before adulthood [10]: 33–53% [7,13] require subepicardialpacemaker in the neonatal period; in the late ages, this percentile raisedto 60% [10,13]. The CHB mortality is variable from 12% to 43% in litera-ture [8,13–16] and it increases when the disease is associated withendocardial fibroelastosis or cardiomyopathy [17]. When CHB is diag-nosed, an intrauterine therapy is possible to increase the atrioventricularconduction speed and improve the fetal outcome. Maternal treatmentwith fluorinated steroids, as dexamethasone or betamethasone, can re-duce the antibody-mediated inflammatory damage of nodal tissue. Thealternatives/additional therapies include the plasmapheresis, intrave-nous immunoglobulins and betasympathomimetics [18].
However, excluding the reports on CHB, the study results onpregnancy outcome of women with pSS are few and conflicting.Two series have reported increased rate of spontaneous abortionsand fetal losses [19,20] not related to anti-SSA, anti-SSB, or anti-phospholipid antibodies. Other studies did not confirm these data,but underlined that pregnant women with pSS had more advanced age,with offspring having a high rate of SGA and lower mean birth weight.Furthermore, less frequency of normal partus was observed [21].
For other autoimmune diseases, the impact on pregnancy outcome iswell established and it differs according to the maternal disease, diseaseactivity, severity of organ damage, antibody profile and drug treatment[22]. Among autoimmune diseases, systemic lupus erythematosus (SLE)and antiphospholipid syndrome (APS) have been widely studied fortheir detrimental effects on fetal and maternal health, showing a higherrisk of fetal losses, premature deliveries, preeclampsia, and IUGR[22–28]. It is also noteworthy that some obstetrical complications mayprecede the clinical onset of connective tissue diseases [29] or indicatethe presence of underlying autoimmune diseases [30].
These issues have not been carefully addressed in pSS, prompting usto perform a review of the literature on pregnancy outcome in womenwith pSS, including our case–control study. In order to clarify if thepreg-nancy outcome was affected by the disease clinical onset, in our series,data of pregnancy before and after pSS diagnosis were analyzedaccording to the timing of pSS diagnosis.
2. Materials and methods
Thirty-four pregnancies in 22 women with pSS, followed at ourtertiary referral center between 2002 and 2012, were retrospectivelycollected. All the included patients fulfilled the American EuropeanConsensus Criteria (AECC) for pSS [31].
In addition, one hundred and thirty six healthy pregnancies wereevaluated as controls. Data about pregnancy outcome in both groupswere obtained from electronic case records of our center. In particular,the number of spontaneous abortions (≤20 weeks of gestation), still-births (the intrauterine death N 21th week of gestation and beforebirth), fetal losses (the sum of spontaneous abortions and stillbirths),preterm deliveries (b37 + 0 week of gestation), low birth weight neo-nates (LBW: defined as birth weight b 2500 g) and IUGR (defined as abirth weight percentile b 10th according to a national standard curve)[32] were analyzed as indicators of obstetric outcome. The following in-formations were also extracted from the delivery register and evaluatedin the twogroups:way of delivery, gestationalweek at delivery, neonatalbirth weight, and neonatal birth weight percentile.
The serum immunological profile of women affected by pSS duringpregnancywas also analyzed. Patientswere profiled for the following an-tibodies: anti-nuclear antibodies (ANA, detected by immunofluorescence
analysis; ANA titer is positive when it is ≥1:80) and anti-Ro (SSA)and La (SSB) cellular antigen antibodies (detected by ELISA; theirtitles were positive in case of ≥25 UI/ml). In addition the presenceof rheumatoid factor (RF), anti-double stranded DNA IgG antibodies(anti-dsDNA, detected by ammonium sulfate precipitation accordingFarr), anti-cardiolipin IgG and IgM antibodies (aCL, detected byELISA), anti-beta2 glycoprotein I IgG and IgM antibodies (antiβ2GPI,detected by ELISA) and Lupus anticoagulant (LA, determined by activatedpartial-thromboplastin time, aPTT-, aT dilutedwith phospholipids, Kaolintime and tissue thromboplastin inhibition test) were assessed.
Normally distributed continuous variables were compared using atwo-sample Student t test. Cross tabulation and Chi-square (with Yates'continuity correction) were used to examine the relationship betweennominal variables. P b 0.05 was considered statistically significant.
3. Results
3.1. Demographic data
Maternal age at deliverywas significantly higher inwomenwith pSS(mean = 34.8 years) vs controls (30.2 years; P = 0.0005).
Among the 34 pregnancies, in the 22womenwith pSS, six pregnan-cies (18%) occurred before the pSS diagnosis and 28 (82%) after the pSSdiagnosis. In the 6 pregnancies that occurred before the pSS diagnosis,the time between the index pregnancy and the disease diagnosis was6.6 years; whereas, in the 28 pregnancies that occurred after the pSSdiagnosis, the mean disease duration was 4.1 years.
As regards thewomenwith pSS diagnosis before pregnancy, no caseof systemic diseasewas observed during pregnancy; no patientwas alsoreceiving cytotoxic drugs during or before pregnancy. According to theirdisease clinical state, these women received specific medical treatmentduring pregnancy, consisting of steroids in 12 cases (43%), and anti-malarian drugs in 13 cases (46%) with or without steroids. Low-doseaspirin was administered in 13 cases (46%).
In the 28 pregnancies that occurred after the pSS diagnosis, the inci-dence of ANA and Ro/SSA positivity was 82% and 100%, respectively.Anti-La/SSB and RF were positive in 61% and 36%, respectively. Finally,39% of the pSS patients had one or more antiphosholipid antibody(aPL) positivity, but no case fulfilled the revised classification criteriaof APS [26].
3.2. Pregnancy outcome
Among the 34 pregnancies inwomenwith pSS, 10 pregnancies (29%)ended in spontaneous abortions, and no case of stillbirth was registered.One voluntary abortion (3%)was observed in a case complicated by fetaldiagnosis of Klinefelter syndrome. So, the live birth rate consisted of 68%.
The results of pregnancy outcome in 34 patients with pSS comparedto that in 136 controls are shown in Table 1. The obstetrical outcome interms of mean week at delivery, mean neonatal birth weight and meanneonatal birth weight percentile was encountered in pSS patients incomparison to that of controls, as shown in Table 1.
Two pregnancies (9%)were complicated by CHB: they occurred afterthe pSS diagnosis. In the first case with CHB, a Chickenpox infectioncomplicated the pregnancy in the first trimester, requiring the reduc-tion of the ongoing steroid treatment. By serial fetal echocardiographicevaluation, a third degree intrauterineAVblockwas identified at 24 ges-tational weeks, so the treatment with high-dose betamethasone wasstarted. A preterm delivery (31th gestational week) was needed be-cause of fetal distress, with a live female infant weighting 1210 g(Apgar score 71, 85). The neonate required a pace-maker implantationwithin the first 12 h of life; at 5 years follow up, she is in good health.In the second case, the CHB was diagnosed at 22 gestational weeks;then, high-dose betamethasone was administered. This pregnancyended with a delivery at the 32nd gestational week of a live female
Table 1Pregnancy outcome according to the timing of primary Sjogren's syndrome (pSS)diagnosis.
Controlsn = 136
Totalprimary SSn = 34
Pregnancies
After pSSdiagnosis
Before pSSdiagnosis
n = 28 n = 6
Spontaneous abortion (%) 4/136 (3) 10/33 (30) 9/27 (33) 1/6 (17)P-value b0.0001 NSPreterm delivery≤37 wks (%)
7/132 (5) 9/23 (39) 6/18 (33) 3/5 (60)
P-value b0.0001 NSIUGR (%) 2/132 (2) 1/23 (4) 1/18 (6) 0/5 (0)P-value NS NSBirth weight b2500 g (%) 1/132 (1) 8/23 (35) 5/18 (28) 3/5 (60)P-value b0.0001 NSCesarean section (%) 41/132 (31) 13/23 (57) 8/18 (44) 5/5 (100)P-value 0.03 0.02Birth weight (g)(mean ± SD)
3360 ± 460 2625 ± 654 2643 ± 612 2558 ± 868
P-value b0.0001 NSBirth weight percentile(mean ± SD)
56.3 ± 24.6 35.2 ± 22.3 33.3 ± 21.2 41.8 ± 27.6
P-value 0.0002 NSWeek at delivery(mean ± SD)
39.8 ± 1.5 37.1 ± 3.3 37.4 ± 3.2 36.0 ± 3.5
P-value b0.0001 NS
wks = weeks of gestation.
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infant weighting 1500 g, who died in the first day of life, despite thepacemaker implantation.
In order to investigate the impact of pSS diagnosis on pregnancy out-come, data from pregnancies that occurred before pSS diagnosis werecompared with those from pregnancies that occurred after the diseasediagnosis. No difference in perinatal outcome in terms of mean weekof delivery,mean neonatal birthweight andmeanneonatal birthweightpercentile was found (Table 1). Similarly, the number of spontaneousabortions, IUGR, LBWand pretermdeliveries was not statistically signif-icantly different between the two groups (Table 1).
To underline the role of the aPL antibody positivity, pregnancy out-come in terms of fetal losses, preterm deliveries, birth weight and birthweight percentile was investigated: no difference was encountered be-tween women with and without aPL antibodies positivity.
4. Discussion
Autoimmunediseases are known to occur predominantly inwomen.The fertility seems not to be impaired, so pregnancies complicated bythese disorders are of high clinical impact for both obstetricians andrheumatologists [19,33].
Data on pregnancy outcome in pSS are few and conflicting until now.In the past decades, the paucity of reportsmay be related to the fact thatpSS does not usually become clinically apparent until the fourth decadeof life. However, in more recent years the advanced maternal age of thefirst pregnancy can explain the increased impact of pregnancies compli-cated by pSS.
The few studies that have evaluated the pregnancy and fetal out-come in patients with pSS used older classification criteria and differentdata resources: questionnaire and interview [19,33], delivery registry[21], and combined questionnaire and birth registry data [34]. The in-creased interval between pregnancy and questioning, over reportingdata and the absence of miscarriage registry are the principal bias ofthese data resources. In our series data about pregnancy outcomewere obtained from electronic case records, increasing the accuracy ofthe details. Furthermore, different definitions for pregnancy complica-tions are employed in these studies.
Our results indicate that women with pSS experienced complicatedpregnancies more frequently than controls. In particular, these women
showed a higher incidence of spontaneous abortions than controls,according to some previous results [19,20] (Table 2). The lower rateobserved by other authors is probably due to the study design and thedata resources: surprisingly, in some of these papers, the rate of sponta-neous abortions in women with pSS is less than that observed in thegeneral population [36].
The observed increased rate of spontaneous abortions [19,20, presentstudy] (Table 2) may be firstly explained by the older age of the patientsversus that of controls, secondly by the fact that younger women withpSS often suffer of more severe disease, determining a delayed planningof their first pregnancy. Finally, it should be noticed that an immunolog-ical disturbance may be involved in the mechanisms of miscarriage.However, our results failed to demonstrate a crucial role in the etiologyof miscarriage of the aPL antibody positivity.
As regards the rate of induced abortions, an extreme variability of thisparameter is described in women with pSS, ranging from 2% to 36%[33,35,37] (Table 2). In our opinion, the different counseling to thewomen on thematernal and feto-neonatal risks, the different geographicareas and socio-economic conditions could interfere with this choice.
It is also noteworthy that the rate of preterm deliveries was consis-tently more prevalent in our patients than in controls, in agreementwith two recently published studies [21,37] (Table 2). In addition,according to Hussein et al. [21], the rate of LBW infants and cesareansection was significantly higher in the patients compared with that ofcontrols. The other studies lacked to report these findings (Table 2).
In our series, the difference of IUGR rate between pSS patients andcontrols did not reach the statistically significant difference, probablydue to the small number of cases. In addition, the mean neonatal birthweight and themean neonatal birthweight percentile were significantlylower in offspring of pSS mothers in comparison to those of controls.Similarly, Hussein et al. [21] emphasized that the mean birth weightwas statistically significantly lower in offspring of pSS mothers(3010 g) vs babies of controlmothers (3458 g) (P = 0.025). It is very in-triguing that in our study the mean neonatal birth weight percentileresulted lower in babies born to pSS mothers than in those born to con-trols. This finding is of peculiar relevance: the birth weight percentile,differently from the birth weight, is a direct measure of the fetal growth:so, a lower birthweight percentile is directly related to a pathological in-trauterine growth restriction and it is not influenced by the timing of thedelivery. The anxiety of the physician and/or thewoman could lead oftento anticipate the timing of delivery, justifying a lower neonatal birthweight, but not a lower birth weight percentile, if the intrauterine fetalgrowth is normal.
Themechanism of the reduction of the neonatal birthweight percen-tile in women with pSS could be an underlying placental insufficiency,related to the immunological disturbance.
In order to clarify if the pregnancy outcome was affected by thedisease clinical onset, data of pregnancy before and after pSS diagnosiswere analyzed. Unexpectedly, no difference was detected in the preg-nancy outcome before and after pSS diagnosis. Previously, Husseinet al. [21] found similar pregnancy outcome inwomenwith pSS diagno-sis before or after the index pregnancy, attributing these results to apossibly low statistical power of the small case number.
5. Conclusions
In our opinion, all thesefindings suggest that the underlying autoim-mune disorder, whichmay be already present before the pSS diagnosis,significantly affects pregnancy outcome. In other words, the immuno-logical status of these women present throughout the reproductive liferegardless of symptoms can interfere with the physiological develop-ment of the placenta and fetal growth.
Taking into account the aforementioned observations, the role ofa multidisciplinary approach with rheumatologists, obstetricians andpediatricians would be hopeful for the optimal management of preg-nancies complicated by pSS.
Table 2Pregnancy outcome in women with Sjogren's syndrome: review of the literature.
Authors Study design Pregnanciesn
Spontaneousabortions (%)
Stillbirths(%)
Inducedabortions (%)
IUGR(%)
Prematuredeliveries (%)
Live births(%)
Siamopoulou-MavridouA et al. (1988)
Retrospective study with questionnaire 63 13 (21) 2 (4) NR NR 0 48 (76)
Takaja M et al. (1991) Retrospective study with questionnaire 39 2 (7) 0 9 (23) NR 1 (4) 28 (93)Skopouli FN et al. (1994) Retrospective study with questionnaire 207 18 (14) 3 (3) 75 (36) NR 2 (2) 111 (84)Julkunen H et al. (1995) Retrospective study with records and interview 55 10 (18) 1 (2) NR 1 (2) 1 (2) 44 (80)Hussein SZ et al. (2011) Case–control delivery registry linkage study 16 Lacking 1 (6) NR 4 (25) 2 (13) 15 (94)Priori R et al. (2013) Case–control delivery registry linkage study 45 4 (9) 0 1 (2) NR 6 (15) 40 (91)Present study (2013) Electronic case records 34 10 (30) 0 1 (3) 1 (4) 9 (39) 23 (70)
Total (%)a 459 57/357 (16) 7/316 (2) 86/325 (26) 6/84 (7) 21/316 (6) 309/373 (83)
Definitions: NR = not reported. The percentages are in brackets. (Hussein) Spontaneous abortions are lacking; premature deliveries: b37 + 0 wks; low birth weight: b2500 g;(Julkunen) spontaneous abortions: b12 wks; induced abortions were excluded; stillbirths: N22 wks; premature deliveries: b37 + 6 wks; (Moutsopoulos) spontaneous abortions:b20 wks; stillbirths: N21 wks; premature deliveries: 21–37 wks; (Takaya) not explained in the text; (present study) spontaneous abortions: ≤20 wks; stillbirths: N21 wks;premature deliveries: b37 + 0 wks.
a Total: for spontaneous abortions, the total is calculated on overall pregnancies without induced abortions; for stillbirths, it is calculated on overall pregnancies without inducedabortions plus spontaneous abortions; for induced abortions, it is calculated on overall pregnancies; for IUGR, it is calculated on overall pregnancies without induced abortions plusspontaneous abortions; for premature deliveries, it is calculated on overall pregnancies without induced abortions plus spontaneous abortions; and for live births, it is calculated onoverall pregnancies without induced abortions.
106 S. De Carolis et al. / Autoimmunity Reviews 13 (2014) 103–107
In the future, a prospective observational and multicenter studywould be necessary to better clarify the impact of pSS on pregnancyoutcome.
Take-home messages
• Women with pSS experienced complicated pregnancies morefrequently than controls: in particular, these women showed a highincidence of spontaneous abortions, preterm deliveries and LBW in-fants. Surprisingly, any difference in pregnancy outcomewas detectedbefore and after pSS diagnosis.
• The underlying autoimmune disorder, which may be already presentbefore the pSS diagnosis, significantly affects pregnancy outcome andcan interfere with the physiological development of the placenta andfetal growth, regardless of the presence of the disease clinical symp-toms.
• Amultidisciplinary approach with rheumatologists, obstetricians andpediatricians would be hopeful for the optimal management of preg-nancies complicated by pSS.
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Antimuscarinic acetylcholine receptor-3 (m3AChR) autoantibodiesM, et al. (Neuroimmunomodulation 2013;20:79-86) compared vaof anti-m3AChR and other immunological and psychosocial factorsmatoid arthritis (RA) patients, 103 systemic lupus erythematosus (SThree immunodominant epitopes of m3AChR were synthesized andin fusion with glutathione-S-transferase and one in conjugation withthe 36-item Short-Form Health Survey and Functional Assessment ouated between glandular function and anti-m3AChR positivities andeters. Fourteen RA and 27 SLE patients had sSS. The autoantibodypSS and SLE patients than in the controls. The fusion protein formfusion protein also distinguished pSS from SLE. The prevalence anbetween sicca and non-sicca SLE or RA patients.
Neuroimmune interactions in Sjögren's syndrome: relationship ofacetylcholine receptor-3 and mental health status parameters.
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come of pregnancy in Italian patients with primary Sjögren syndrome. J Rheumatol2013;40:1143–7.
have been described in primary Sjögren's syndrome (pSS). Deákrious methods for their detection and to assess the contributionsto the pathomechanism of secondary SS (sSS). Sixty-five rheu-LE) patients, 76 pSS patients and 50 controls were compared.used in ELISA. Two extracellular epitopes were also preparedbovine serum albumin. Mental health status was assessed withf Chronic Illness Therapy fatigue scale. Correlations were eval-specificities, features of SLE and RA, and mental health param-levels to all epitopes of m3AChR were significantly higher ins discriminated RA from pSS and SLE; furthermore, the YNIPd the mean levels of all autoantibodies did not differ statistically
exocrine gland dysfunction with autoantibodies to muscarinic