Abstract
The 12th International Congress on Antiphospholipid Antibodies and the 5th International Conference on Sex Hormones, Pregnancy and Rheumatic Diseases offered the unique opportunity to bring together the world leaders in the field of pregnancy and rheumatic diseases. The management of pregnancy in women suffering from rheumatic diseases is becoming a common clinical situation. Moreover, we now have more information on the pathogenic mechanisms responsible for pregnancy complications: negative pregnancy outcomes, disease flares and consequences of the mother's disease or treatment on the offspring. A specific and interdisciplinary expertise is required to avoid such manifestations. An additional aspect is represented by the use of the newly introduced antirheumatic drugs.
The correct pregnancy planning, the use of widely validated therapeutical regimens and the careful administration of safe drugs can offer the chance for term pregnancies in rheumatic patients. The program, which attracted attendees from 50 different countries, was drafted by an international committee, co-chaired by Pier Luigi Meroni (University of Milan, Milan, Italy), Angela Tincani (University of Brescia, Brescia, Italy), Maurizio Cutolo (University of Genoa, Genoa, Italy) and Marco Matucci Cerinic (University of Florence, Florence, Italy). The aim was to provide physicians with updated information on the management of pregnancy in women suffering from autoimmune diseases.
The conference was organized in combination with the 12th International Congress on Antiphospholipid Antibodies. Antiphospholipid antibodies (aPL) are in fact one of the most frequent causes of pregnancy complications in autoimmune patients, but are also one of the few known causes of pregnancy loss in the general population. Miscarriages and other obstetrical complications represent one of the most important features of the antiphospholipid syndrome (APS) and are formal classification criteria for APS.
Most of the systemic autoimmune diseases display a high female:male ratio and have their peak of incidence in the childbearing age. Moreover, the improved prognosis of systemic autoimmune diseases favors a planned pregnancy. Hence, pregnancy in women suffering from systemic autoimmune diseases is becoming a clinical situation more and more common.
The problem of pregnancy in autoimmune patients can be addressed from different points of view:
The effect of the disease itself on the pregnancy outcome
The effect of pregnancy on the disease course
The effect of the disease – or its treatment – on the offspring.
Key presentations
Friday the 20th of April was the day shared in common by the two meetings and was focused on the obstetric aspect of APS. Several speakers reported data that confirmed the association between aPL – in particular lupus anticoagulant (LA) – and miscarriages or pregnancy complications.
W Branch (University of Utah, UT, USA) confirmed that late fetal death represents a typical feature of APS, being very rare in healthy women (3 vs 10% of incidence). He also raised the issue of whether or not early fetal losses really represent a pathological manifestation because of their high frequency even in the general population (ranging between 12 and 15%).
Although there is no evidence for an increased incidence of LA or anticardiolipin antibodies (aCL) in women who experienced eclampsia or hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, A Lojacono (University and Hospital of Brescia, Brescia, Italy) provided data confirming that aPL-positive patients display a high risk for developing these pregnancy complications.
Several in vivo and in vitro studies, presented during the section, addressed the potential pathogenic mechanisms by which aPL can induce recurrent fetal loss. Thrombotic events at the placental level may explain the aPL fetal losses only in part. Actually, there is strong evidence that aPL (and in particular β2 glycoprotein I [β2GPI]-dependent antibodies) bind to the trophoblast, affecting its proliferation and differentiation into a mature and invading syncytiotrophoblast. Moreover, data presented by R Rai (Imperial College London, UK) and MO Borghi (University of Milan, Milan, Italy) strongly suggested that aPL (and in particular anti-β2GPI antibodies) can affect not only the fetal part of the placenta, but also the maternal one. Anti-β2GPI antibodies were actually shown to react directly with human decidual cells in vitro and to upregulate the expression of adhesion molecules (ICAM-1) and the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF). Altogether, these findings suggest that aPL may interact directly with different placental structures, affecting their functions and inducing a defective placentation through a local inflammatory process. In line with this are the data presented by MD Lockshin (Cornell University, NY, USA) on the role of complement in these events. aPL antibodies may in fact induce complement activation that leads to an increased expression of several adhesion molecules, recruitment of inflammatory cells, and local secretion of pro-inflammatory mediators. The placental inflammation that results from this sum of events is apparently essential for aPL-mediated fetal loss in experimental animals. In fact, mice deficient in complement components or treated with C3 inhibitors or C5-blocking antibodies are protected from the fetal loss induced by the infusion of aPL. Interestingly, other pro-inflammatory molecules – such as chemokines – are apparently important in this process as shown by the higher susceptibility to aPL-mediated fetal loss of mice deficient for D6, a chemokine scavenger receptor that recognizes and targets for degradation most inflammatory CC chemokines (Y Martinez de la Torre, Istituto Clinico Humanitas, Milan, Italy).
Several reports confirmed the efficacy of heparin and low-dose aspirin (LDASA) in the prevention of aPL-asso-ciated pregnancy complications. However, the pathogenic role of mechanisms other than thrombosis raises the issue of which is the pharmacological effect of heparin and LDASA responsible for the clinical efficacy of such treatment. For example, heparin was shown to be able to reduce anti-β2GPI antibodies binding to phospholipids, to inhibit trophoblastic cells' apoptosis, complement activation and to promote endometrial decidualization. Thus, heparin may display a pleiotropic pharmacological effect besides the well-known anticoagulant activity. Moreover, ASA has been also proved to inhibit cell apoptosis.
The last part of the session approached clinical aspects in the treatment of the obstetrical manifestations of APS. While there is a general agreement that heparin (either unfractionated or low-molecular-weight heparin [LMWH]) and LDASA do represent the standard therapy, there are controversies in specific situations. For example, the treatment of pregnant patients with APS and previous thrombosis has not been fully clarified. RHWM Derksen (University Medical Center, Utrecht, The Netherlands) reported that these patients must be treated with oral anticoagulants in order to prevent recurrences (whose incidence was reported in 2.4% of the series). Oral anticoagulant drugs must be stopped in the first 6 weeks of gestation and shifted to heparin at the full dose during pregnancy until 24 h before programmed delivery. NR Jesus (Universitade de Estado do Rio de Janeiro, RJ, Brazil) presented an interesting study evaluating the use of warfarin instead of the standard therapy (heparin plus LDASA) in APS pregnancy. Treatment with warfarin between the 14th and the 35th week of gestation was shown to be safe and with a successful outcome rate comparable to that of the heparin plus LDASA scheme. Such a therapeutic option is cheaper and easier to administer. Another hot topic regarding therapy was discussed by Lockshin, who reported the results of a questionnaire prepared together with A Tincani and distributed it to 26 APS specialists (gynecologists, rheumatologists, internists). The questionnaire was concerning how to treat those cases for which there are no clinical trials available. Most of the experts suggested to increase the heparin dose to therapeutic regimen to pregnant APS patients, who experienced midpregnancy fetal loss despite treatment with heparin plus LDASA. If the same patients were already receiving a therapeutic heparin regimen, most experts agreed on the addition of intravenous immunoglobulin (IVIg) and/or a low dose of corticosteroids. In a similar way, dealing with aPL-positive pregnant women not fulfilling the APS Sydney classification criteria, the most diffuse attitude was to treat all the pregnant patients, even asymptomatic, with LDASA and to add heparin only to women with a history of at least two early fetal losses. A similar advice was given for aPL-positive patients undergoing ovarian hyperstimulation for IVF. Oral contraceptives are mostly contraindicated in patients affected by APS or in asymptomatic women with persistent positivity for aPL. The last question referred to the duration of thrombosis prophylaxis in APS patients after delivery: most of the experts suggested to continue the treatment for 4–6 weeks or more in the puerperium period. In other words, the ‘real life’ practice among experts is suggesting a slightly more aggressive therapeutic approach in comparison with the previous guidelines.
Finally, HJA Carp (Sheba Medical Center, Tel Hashomer, Israel) addressed the issue of the association between aPL and infertility. The association is still controversial, but aPL may be reasonably responsible for some cases.
Is the APS just a maternal disease? If aPL are pathogenic autoantibodies, the transplacental passage of aPL IgG should be responsible for damage in the fetus too.
Fortunately, this is the exception rather than the rule, and ischemic events in fetuses or neonates are anecdotic as reviewed by E Lachassine (Hopital Jean-Verdier Bondy and Université de Paris XIII EA, France) who presented data from a multicenter international register of babies born from mothers affected by APS. A very low rate of thrombotic or autoimmune features was found in spite of the fact that aPL could be detectable in up to 50% of the babies during the first months of life. In some cases anti-β2GPI can appear after delivery from the 4th to the 18th month, maybe due to weaning, vaccination or concomitant infections. Besides their thrombogenic effect, aPL have been shown to induce a direct neuronal damage in experimental models. Accordingly, Tincani reported a neuro-psychological study in children of aPL-positive mothers that found a significant incidence of learning disabilities (26.7%) in a series of 15 children.
Another cause of neonatal disease is the so-called neonatal lupus syndrome. Neonatal lupus syndrome was the topic of the first session of the 5th International Conference on Pregnancy, Sex Hormones and Rheumatic Diseases that started on Friday 20th of April in the evening. R Clancy (New York University School of Medicine, Hospital for Joint Diseases, NY, USA) and S Salomonsson (Sweden) reported on the pathogenic mechanisms responsible for the most severe feature of neonatal lupus: the congenital heart block (CHB). Maternal anti-Ro/SSA and anti-La/SSB autoantibodies are suggested to recognize fetal cardiac antigens and to activate macrophages with an increased production of pro-inflammatory (TNFα) and fibrogenic (transforming growth factor [TGF]β) cytokines. The process would lead fibroblasts' differentiation and activation with consequent tissue fibrosis and hypoxia. The low percentage of anti-Ro/SSA- and anti-La/SSB-positive mothers that develop CHB in the babies does suggest that fetal factors (genetic factors) are also playing a role. Additional environmental factors seem to be important: children with CHB had higher levels of erythropoietin in cordon flow, as a consequence of cardiac hypoxia. The hypoxic response of cardiac tissues may facilitate the production of growth factors that in turn increase the fibrosis. There is a general agreement on the need for correct counseling for the mothers and of performing a fetal echocardiography from the 2nd to the 16th week of gestation. In the case of atrioventricular block, the mother must be treated with oral β-meth-asone. β-agonists or IVIg are used when the cardiac rate is lower than 55 beats/min or in case of concurrent myocarditis, respectively. However, there are no clinical studies up to now. Some authors suggested the use of IVIg in order to prevent recurrences (10–20-times more frequent) in mothers with CHB in a previous pregnancy.
Saturday 21st of April was dedicated to the problem of pregnancy in the other systemic autoimmune diseases.
Patients affected by systemic lupus erythematosus (SLE) frequently experienced disease relapse during pregnancy, usually characterized by mild cutaneous and articular features. The number of flares before pregnancy seems to be a predictive factor, while a longer duration of the disease is supposed to protect from flares. Approximately 30% of women with a history of lupus nephritis develop a renal flare during pregnancy: the outcome can be predicted by the renal disease at conception (A Doria, University of Padua, Padua, Italy).
Scleroderma does not seem to influence pregnancy outcome, but the cardiovascular modifications occurring during pregnancy can cause several scleroderma complications. Scleroderma pregnant women may complain for arthralgias, gastro-oesophageal reflux and dyspnoea. More severe complications, such as scleroderma renal crisis, ventricular arrhythmias and heart failure are rare, but should be taken into consideration. Preterm delivery and small full-term babies frequently occur, especially in early diffuse scleroderma (M Matucci Cerinic).
Rheumatoid arthritis (RA) usually improves during pregnancy. M Østensen, F Forger and PM Villiger (all University Hospital of Bern, Bern, Switzerland) discussed the mechanisms behind this phenomenon in detail. During pregnancy, a dramatic change of cytokine profile occurs, with the prevalent expression of Th2 lymphocytes resulting in a noninflammatory milieu. Some studies have also demonstrated that maternal–fetal HLA disparity facilitates RA improvement. It has been suggested that placental apoptotic syncytiotrophoblast debris –containing fetal HLA II peptides – is present in the maternal blood during pregnancy. Immature maternal dendritic cells can then simultaneously present fetal and self RA-associated antigens to T lymphocytes in the setting of a noninflammatory environment. This process was suggested to play a role in inducing fetal tolerance and RA improvement. M Cutolo reported that changes in sex hormones can increase Th2 cytokines and consequently modulate the immune response, favoring the clinical improvement. In addition, regulatory T lymphocytes (CD4+, CD25+ and Foxp3+), usually inhibited in RA by elevated levels of TNFα, can be reactivated during the pregnancy, suppressing autoreactive T lymphocytes and inducing a tolerogenic milieu.
A lecture on leflunomide in pregnancy was presented by CD Chambers (OTIS Collaborative Research Group, CA, USA) on behalf of an American collaborative research group. Leflunomide is formally contraindicated in women in childbearing years, since a teratogenic effect was found in animal models. Chambers presented the results of the prospective study on the adverse effects of accidental in utero exposure of fetuses to the drug. Preterm deliveries were more frequent in the exposed group, but the rate of major structural malformations in the newborns was the same as in the nonexposed group (7.4 vs 6.3%). Nevertheless, a wash out from the drug is strongly recommended before conception.
The meeting was closed by Østensen, who presented a consensus report on the use of newly introduced antirheumatic drugs. The session aimed to give practical suggestions to physicians dealing with the management of rheumatic pregnant women in the daily practice. Østensen discussed the management of RA women with different immunosuppressive drugs before pregnancy. Anti-TNFα (infliximab, etanercept and adalimumab) and anti-B lymphocyte (rituximab) compounds cross the placenta at the 14th week of gestation. Approximately 150 cases of infliximab-exposed pregnancies were reported with the same outcome of nonexposed women in terms of miscarriages, preterm delivery and congenital malformations. Two miscarriages, one hip dysplasia and 21 healthy newborns were reported in 24 adalimumab-exposed pregnancies. Among 78 etanercept-exposed pregnancies, a woman (who received 100 mg of etanercept/week) delivered a baby with Vater syndrome, featuring multiple gastroenteric, vertebral and kidney malformations. A total of four cases of pregnant women treated with rituximab were reported: a low B-lymphocyte count was detected in all the babies, without occurrence of particular consequences. In clinical practice, it is mandatory to stop infliximab, etanercept and adalimumab at conception, while rituximab must be stopped approximately 12 months before pregnancy. Methotrexate must be withdrawn at least 3 months before conception, while mycophenolate–mophetile must be stopped 6 weeks before conception due to reported hand malformations. Cyclosporine is permitted during pregnancy, even if some cases of maternal cholestasis and prematurity are reported by an American registry of 2400 pregnancies exposed to cyclosporine. No definitive data are available regarding the detection of anti-TNFα drugs in maternal milk; however, all the Ig classes could be present, so breast feeding is not recommended during treatment, as well as for cyclosporine.
Future perspective
The new information on the pathogenic mechanisms mediated by aPL may offer innovative therapeutic tools for preventing miscarriages and for improving the prognosis. This could be the case for compounds able to inhibit complement activation or the pro-inflammatory cytokines. In addition, synthetic peptides competing with the main antigenic target of aPL are promising molecules potentially able to block the autoantibody effect in vivo in a safer way.
New and very effective antirheumatic drugs have been introduced and more compounds are going to be validated. The future challenge will be to validate their use during pregnancy in order to improve the treatment of maternal systemic autoimmune diseases in a safe way.
To learn more
The abstracts of the meetings have been published in the journal Clinical Experimental Rheumatology 25(2) (2007).
Highlights
Pregnancy in women suffering from rheumatic diseases is a common condition nowadays.
Antiphospholipid antibodies (aPL) represent the most important treatable cause of miscarriages and obstetrical complications.
Widely validated therapeutic schemes are effective in protecting against the risks associated with aPL.
Careful pregnancy planning is mandatory to avoid negative outcome or flares of the autoimmune disorder in the mother.
Specific monitoring protocols have been suggested in order to avoid severe effects of the maternal autoimmune disease on the offspring (as in the case of neonatal lupus syndrome).
The newly introduced antirheumatic drugs raise the need for specific studies on their safety during pregnancy.