Bonnie L. Bermas1 and Lisa R. Sammaritano2
(1)
Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
(2)
Division of Rheumatology, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY 10021, USA
Bonnie L. Bermas
Email: bbermas@partners.org
Introduction
Sjogren’s syndrome (SS), mixed connective tissue disease (MCTD), and undifferentiated connective tissue disease (UCTD) are some of the less common disorders seen in rheumatology. Like many of the other rheumatologic diseases, these disorders have a higher incidence in women; thus, reproductive issues are part of the management of these patients. This is less the case in those patients with Sjogren’s syndrome, as this disorder predominately impacts women towards the end of their reproductive years. Because of the age distribution of Sjogren’s and the relative rarity of MCTD and UCTD, there is a paucity of information on pregnancy outcome and the impact of pregnancy on maternal disease in patients with these syndromes. Nonetheless, some conclusions about these disorders during pregnancy can be drawn from the current literature. This chapter will discuss the pregnancy outcomes in individuals with these disorders and what is known about how pregnancy impacts disease activity.
Sjogren’s Syndrome
Relatively rare (prevalence rate of 4/100,000), Sjogren’s can be seen as an entity unto itself (Primary Sjogren’s, 70 %) or in conjunction with other rheumatologic disorders (Secondary Sjogren’s, 30 %). Manifestations of Sjogren’s include keratoconjunctiva sicca, vaginal dryness, sinusitis, some types of renal tubular acidosis, peripheral neuropathy, and CNS disorders. Generally, the diagnosis is made by a Schirmers test confirming decreased lacrimal flow and a salivary gland biopsy that reveals a characteristic lymphocytic infiltrate. In 60 % of the cases, patients have the anti-Ro/SS-A and/or anti-La/SS-B antibodies [1].
Anti-Ro/SS-A and anti-La/SS-B antibodies are the pathogenic antibodies in congenital complete heart block (CCHB) and neonatal lupus, and so concern regarding autoantibody transfer to the offspring is the major pregnancy risk in antibody-positive Sjogren’s syndrome patients. This topic is discussed in detail in Chap. 13. Nonetheless it is important to note that often it is the birth of a child with CCHB that first prompts the search for these autoantibodies in an otherwise asymptomatic mother. Thus, sometimes pregnancy complicated by CCHB is the trigger for the investigation and diagnosis of Sjogren’s syndrome and other connective tissue diseases [2].
Mixed Connective Tissue Disease
MCTD is a disorder often grouped with systemic lupus erythematosus (SLE) as there is an overlap of symptoms in these diseases. The similarities of the disorders are such that many individuals who are ultimately diagnosed with MCTD are first diagnosed with SLE. Distinguishing features of MCTD include high titer ANA antibodies and the presence of an isolated anti-RNP antibody. Hand swelling, Raynaud’s, myositis, and interstitial lung disease are also key features of MCTD [3].
Undifferentiated Connective Tissue Disease
The term UCTD is generally used to describe those patients who have features strongly suggestive of an autoimmune rheumatologic condition such as Raynaud’s phenomenon, rashes, or an inflammatory arthritis. These patients do not, however, have features that will enable them to be clearly classified into a specific rheumatologic disorder [4]. Estimates of the percentage of patients who will evolve into a clear rheumatologic disorder range from 5 to 35 % [5, 6].
Fertility and Contraception
Sjogrens Syndrome
In general, primary fertility is preserved in women with Sjogren’s syndrome. There have been conflicting data (discussed below) on the presence of secondary infertility, defined as the ability to conceive but subsequent pregnancy loss, in this patient population. In one study comparing 51 patients with primary SS with 57 healthy controls, gynecologic and obstetric histories were reviewed retrospectively. No difference was found between the groups in terms of fertility and parity. However, 40 % of women with SS compared to 3 % of women without Sjogren’s experienced dyspareunia. In only half of these SS patients was the dyspareunia directly attributable to the SS [7]. In another study of 110 patients with primary SS, vaginal dryness did have a negative impact on health-related quality of life, thus patients with SS should be asked about and counseled for this symptom [8]. There are no restrictions in the type of contraception that can be used in women with primary SS unless they have concomitant antiphospholipid antibodies.
MCTD and UCTD
There is no reduction in fertility in individuals with MCTD or UCTD other than the secondary infertility that can be found in some patients who have coexisting antiphospholipid antibodies.
Pregnancy Outcome
Sjogrens Syndrome
There have been conflicting data on the risk of pregnancy loss in SS. One early report retrospectively evaluated the outcomes of pregnancy in women with autoimmune rheumatic diseases including 21 women with primary SS, where pregnancy occurred prior to disease diagnosis. Women with primary SS reported a higher incidence of spontaneous abortion (21 %) when compared to controls [9]. In another study of 55 pregnancies in women with primary SS, 47 pregnancies occurred prior to the diagnosis of primary SS. Twenty percent of the pregnancies ended in fetal loss [10]. The reported increased relative risk of fetal loss of 2.7 was not associated with the presence of anticardiolipin antibodies or antibodies to anti-Ro/SS-A or anti-La/SS-B. In contrast, in a retrospective review of 117 pregnancies in 40 women with Sjogren’s (13 primary SS, 27 secondary SS), the frequency of spontaneous abortions was not higher in this patient group when compared to 129 healthy controls. However, in those patients with coexisting SLE and antiphospholipid antibodies, spontaneous abortions were more common [11].
Pregnancy complications other than CCHB and neonatal lupus seen in anti-Ro/SS-A and anti-La/SS-B positive patients with Sjogren’s syndrome have been reported in small retrospective case series. In one nested case–control series of 16 patients, 10 patients were diagnosed with SS before pregnancy and the six remaining patients were diagnosed after pregnancy. These women’s pregnancies were compared to the pregnancies of 80 healthy women: the mean age at delivery was higher in the SS patients than in controls (33.6 vs. 29.8). While there was no difference in pregnancy duration, there was a slightly increased rate of forceps and cesarean section delivery in the women with primary SS. Reasons for these interventions at delivery were not explored. Additionally, offspring of mothers with SS were of lower weight and more likely to be small for gestational age (SGA) [12]. In a larger case–control questionnaire study, reproductive histories of women with SS were compared to a control population. In this study, only four patients were diagnosed with SS before their last pregnancy, while 58 were diagnosed with SS after all pregnancies were completed. Two patients were never pregnant. The expected rate of CCHB, 3.4 %, was found in the offspring. While preeclampsia, proteinuria, and premature labor were seen more frequently in patients than in controls, this finding was not statistically significant once smokers were excluded from the analysis [13]. In another study of pregnancies in anti-Ro/SS-A positive women who had SLE and other connective tissue diseases, there was no increase of pregnancy complications seen in anti-Ro/SS-A positive women other than CCHB [14].
While there have been some reports of increased spontaneous pregnancy losses in women who ultimately go on to be diagnosed with SS, this data is confounded by its retrospective nature. More frequent complicated deliveries (instrumental and cesarean section) have been reported in women with Sjogren’s syndrome although this finding has not been consistent in the literature and patient and physician preference for mode of delivery is not discussed. Thus, outside of neonatal lupus and CCHB, Sjogren’s syndrome does not appear to impact pregnancy outcome in a significant manner.
Mixed Connective Tissue Disease
There are a handful of case series that explore the outcomes of pregnancy in women with MCTD. In one large study of 22 women who had 96 pregnancies before the diagnosis of MCTD, fertility rate was not different than controls. There were eight elective terminations, 12 spontaneous abortions, and three cases of intrauterine fetal demise (IUFD), leading to a 17 % fetal loss rate. In the 10 patients who had 17 pregnancies after their diagnosis of MCTD, there were four elective terminations, six spontaneous abortions, three cases of IUFD, and four live births [15]. This very high fetal loss rate has not been reported in other series. In Lundberg’s and Hedfors’ study of 20 women who had high titer anti-RNP antibodies, four women had 17 pregnancies before the diagnosis of MCTD and the live birth rate was 88 %. The live birth rate was 78.6 % in those women who had MCTD diagnosed prior to pregnancy [16]. Neither of these rates is above the expected rate of pregnancy loss. In another series of eight pregnancies in six women with MCTD, there were three preterm deliveries, and 63 % of the infants were SGA. There were no fetal losses.
There have been three reports of infants born of mothers who have MCTD with chondrodysplasia punctata manifested by micrognathia and depressed nasal bridge and other skeletal abnormalities [17, 18]. The authors suggest that maternal autoantibodies crossing the placenta may affect normal fetal growth plates. This finding should be interpreted conservatively, however, as it has not been reproduced in larger case series.
The data are inconsistent as to whether MCTD diagnosed prior to pregnancy causes higher rates of fetal loss. Moreover, the existing studies are retrospective, giving rise to recall bias. Due to the limited information in the literature, it is impossible to conclude whether MCTD increases the risk of other pregnancy complications such as preeclampsia, prematurity, and SGA infants. Thus, one can reassure patients that the existing information suggests that pregnancy outcome in women with MCTD appears to be good.
Undifferentiated Connective Tissue Disease
There have been several case series that have looked at pregnancy outcome in patients with UCTD. In one study by Castellino et al., 55 pregnancies in 50 patients with UCTD were followed. There were three miscarriages, two in the first trimester and one loss of a twin in the third trimester. There were five cases of preterm premature rupture of membranes (PPROM), two cases of preeclampsia and two of intrauterine growth restriction (IUGR). Delivery mode was notable for 30 cesarean sections. Reasons for the high cesarean section rate, including patient and physician preference, were not given. Average pregnancy duration was 38.6 weeks and the mean birth weight was 3,190 g. Thus, other than a high cesarean section rate there was not a higher than expected untoward pregnancy outcome [19]. In another study in which 62 women were identified as having UCTD during their first trimester of pregnancy, complications of pregnancy including fetal loss, preeclampsia, and fetal growth restriction as well as premature delivery was 2.81 times more common than in healthy controls [20]. In another case series of 25 pregnancies in 20 patients with UCTD, 88 % of pregnancies were term pregnancies while 12 % ended in first trimester abortions [1]. In one case–control study that compared 41 patients diagnosed with UCTD during the first trimester with 82 controls, the women with UCTD had higher rates of SGA infants (30 vs. 13 %). The rate of overall pregnancy complications including preterm delivery, SGA, preeclampsia, and late fetal loss was 39 % among cases and 13.4 % amongst controls [21]. This group may not be representative of all patients with UCTD, as disease diagnosis occurred in the setting of pregnancy. It is well known that in other connective tissue diseases such SLE, myositis, and vasculitis, disease onset during pregnancy is often related to high disease activity and poor pregnancy outcome.
One recent study evaluated uterine artery Doppler velocimetry and obstetric outcomes in connective tissue diseases diagnosed during the first trimester of pregnancy. In 66 patients diagnosed with UCTD, the patients had increased rated of first trimester bilateral uterine artery notches when compared with controls [22].
While there are limited data on the outcomes of pregnancy in UCTD, there is evidence to suggest that most patients do well, although there are risks of PPROM, preeclampsia, IUGR, and higher cesarean section rate, echoing what is found in other connective tissue disorders.
Impact of Pregnancy on Disease Activity
Sjogren’s Syndrome
There are no large-scale studies evaluating the impact of pregnancy on Sjogren’s syndrome. There was one case report of a women with Sjogren’s disease who presented with acute renal failure due to mesangial proliferative glomerulonephritis at her 20th week of pregnancy. At 28 weeks, she underwent a cesarean section due to PPROM [23]. A healthy baby boy resulted. In another case report, a 35-year-old woman who had Sjogren’s had a pregnancy that was complicated by pericarditis. She was successfully treated with prednisolone 30 mg/day as well as heparin. This patient also gave birth to a healthy baby [24]. While there is insufficient data to conclude how pregnancy impacts disease activity during pregnancy, it is probably best to use the approach applied to other rheumatologic disorders that disease should be in remission at the time of conception.
Mixed Connective Tissue Disease
Pregnancy may impact maternal MCTD disease onset and activity. In ten patients reported by Kitridou, five had their disease onset during pregnancy and three patients had disease flares during pregnancy. Disease manifestations included myositis, synovitis, serositis, and increases in proteinuria [15]. In Lundberg’s and Hedfors’ series of 14 pregnancies in women with high titer anti-RNP antibodies, proteinuria occurred in three patients, thrombocytopenia in one, preeclampsia in two, and deep venous thrombosis (DVT) in one. Despite the high number of complications, the authors concluded that these were not higher than the expected rate of complications [16].
There have been two case reports of MCTD disease exacerbation during pregnancy manifesting as pulmonary hypertension [25, 26]. The limited data suggest that there is a small risk of disease flare during pregnancy.
Undifferentiated Connective Tissue Disease
There are limited data on how pregnancy impacts disease activity in women with UCTD. In one study of 25 pregnancies in 20 women with UCTD, 22 patients completed term pregnancies. Six patients experienced a disease flare. One of the patients evolved into full-blown SLE. The other five patients had mild symptoms including arthritis, fevers, and skin rashes. This flare rate was higher than seen in the nonpregnant control UCTD population over a year (7 %) [1]. Thus, it may be that the immunologic and hormonal changes seen during pregnancy can induce disease activity is some patients with UCTD.
Treatment
As in other rheumatologic disorders, medications may need to be adjusted in anticipation of pregnancy: it seems prudent to make certain that patients are on medications compatible with pregnancy prior to conception. While hydroxychloroquine is not as much the standard of care in individuals with MCTD and UCTD, in those patients being treated with this medication, one can hypothesize that continuation of this medication may potentially improve outcome in a similar fashion as is seen in those patients who have SLE.
Conclusions
While there is limited data on pregnancy in women with Sjogren’s, MCTD, and UCTD, some conclusions can be drawn. In general, fertility seems to be maintained in these patients. Higher cesarean section rates have been reported for unclear reasons and none of the reports in the literature account for patient and physician preference in delivery mode. Although those with increased disease activity in MCTD are at higher risk for pregnancy complications such as preeclampsia and PPROM, those patients whose disease is under control at conception generally fare well. It may be reasonable to consider a pre-pregnancy echocardiogram to screen for asymptomatic pulmonary hypertension in anti-RNP positive patients.
Pregnancy does not seem to contribute to disease activity in Sjogren’s and MCTD. The story of those with UCTD is less clear: potentially, pregnancy may cause patients with UCTD to evolve into more classical connective tissue disorders such as rheumatoid arthritis or SLE. The question of whether pregnancy will trigger development of “full-blown” SLE is a common one posed by patients, and the likely low but finite risk should be discussed.
The same general approach should be used in the management of these patients during pregnancy as in other rheumatic diseases. Ideally, pregnancies should be planned. Disease activity should be minimized for 6 months prior to pregnancy, preferably on medications compatible with pregnancy. Involvement of maternal–fetal medicine and a team approach with the rheumatology and obstetrics services are ideal.
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