Inflammatory rheumatic diseases predominantly affect women. This also includes many young women who would like to have children or who have not yet completed their family planning when they are first diagnosed. These women do not need to give up on their desire to have children forever. Women with rheumatic disease tend to have fewer children than other women, and it often takes them longer to achieve a desired pregnancy. Today, carefully monitored medical treatment and close collaboration between the rheumatologist and the gynaecologist give these women the opportunity to bring a healthy child into the world.
Diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) have far-reaching consequences for the future plans of affected women: In about one fifth of female patients with rheumatoid arthritis (RA), the disease is diagnosed before a first pregnancy. Most female patients with systemic lupus erythematosus (SLE) obtain a diagnosis before their 30th birthday. Many then choose not to have children at all because the risks related to the disease and its treatment seem too great. More than one half of women with RA or SLE have fewer children than they originally wanted . In addition to the personal decision not to have children in the face of chronic disease, reduced fertility in RA patients and increased risk of miscarriage in women with SLE also play a role [2;3].
The hormonal changes caused by pregnancy and the metabolic changes these induce can also affect the immune system, changing the progression of these diseases. Patients with rheumatoid arthritis often improve during pregnancy, while SLE patients often have increased flare-ups [4;5].
The interplay between RA and pregnancy
The changes to the immune system caused by pregnancy have a significant effect on the progression of RA. Onset of the disease can be delayed by pregnancy, as the expectant mother is protected from initial onset (first manifestation) of RA. In contrast, the risk of onset is sharply increased from shortly after birth until about one year after delivery [4;6;7]. The effects of pregnancy on the immune system are maintained over a longer period of time. This effect is so strong that women with a genetic predisposition toward RA have a lower risk of actually becoming ill after having children than if they remain childless.
It often takes longer for women with RA to become pregnant than healthy women, and after diagnosis they have considerably fewer children than healthy women. This is partially due to the fact that affected women only plan a pregnancy once the disease is well under control. However, worry about the effects of the disease and the medications it necessitates on the development of the unborn child may lead the patient to decide against a further pregnancy.
Premature births and the delivery of low birth weight babies are twice as frequent in RA patients than in healthy women, although the numbers of such occurrences are low overall (<10 %) . Women with ACPA-positive RA in particular have an increased risk of complications with pregnancy. Patients with seropositive RA generally experience more aggressive progression of the disease, which could cause more problems over the course of a pregnancy [8-10].
SLE and pregnancy
SLE in itself endangers pregnancy: the risks of miscarriage, pre-eclampsia (“toxaemia of pregnancy”), or premature birth are increased by a factor of three. The causes for this are the existing SLE activity or additional flare-ups, possible involvement of the kidneys, and the occurrence of antiphospholipid antibodies that can cause thrombosis. Even after a successful pregnancy and delivery, complications like more SLE flare-ups or thromboembolisms may occur. SLE patients with associated antiphospholipid syndrome (APS) are particularly at risk. The increased number of miscarriages and worry about both their own health and that of the child contribute to the fact that women with SLE have even fewer children than those with RA [1;11;12].
The fraction of live births in patients with SLE has risen from about 60 % in the 1960s to about 85 % today. However, pregnancy is still tied to an increased risk for mother and child. This is the result of exacerbation of the SLE, a higher number of complications in pregnancy, negative outcomes to the pregnancy, and an increased risk of neonatal lupus in the child. Women with higher clinical and serological activity have the highest risk of complications in pregnancy. In these patients, the first step should be to try to gain control over the activity of the disease with drugs before a pregnancy is planned. Active lupus nephritis also increases the risk of maternal complications and miscarriages, and should be treated before pregnancy [13-15].
One indicator of possible complications is increased disease activity in the first trimester and high antiphospholipid titres. Positive antiphospholipid antibody results are generally associated with increased risk to the pregnancy. Patients with only a single positive test for anti-cardiolipin, anti-beta-2-glycoprotein, or lupus anticoagulant usually have a successful pregnancy, while a triple positive result and high antiphospholipid antibody titres are attended by an increased risk of foetal loss[16;17].
The first results from a large-scale study of pregnancy with SLE, PROMISSE: Predictors of pRegnancy
Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic
lupus Erythematosus) demonstrate that most pregnancies progress with no problems if the SLE is stabilized.
The PROMISSE study was funded by the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health in 2003 to identify biomarkers that would predict poor pregnancy outcomes in lupus patients. To date, the PROMISSE investigative team has enrolled 647 volunteers who are monitored with monthly checkups and research laboratory studies looking at genes and circulating proteins that may predict the course of pregnancy. PROMISSE will continue through 2013 to examine a broad range of genes and molecular pathways that can affect pregnancy in women with lupus, and, it is anticipated that the findings will also have applications for the prevention of miscarriage and preeclampsia in healthy women.
(=>News release from November 5, 2011 about first results of the PROMISSE study)
In cases of SLE, maternal antibodies can endanger the new born child
The overwhelming majority of children of SLE patients are healthy. During active transport of maternal antibodies across the placenta after about the 16th week of pregnancy, antiphospholipid antibodies may also enter the foetal blood stream. A fraction of these children subsequently develop neonatal lupus syndrome with reversible skin lesions. Cardiac involvement in neonatal lupus is more dangerous, usually taking the form of an irreversible congenital heart block or cardiomyopathy. This generally occurs in 2 % of women during their first pregnancy. The majority of these children require a pacemaker. About one fifth of the children with cardiac neonatal lupus die as a result of the accompanying complications. A high titre of maternal antibodies and simultaneous detection of SS-A/Ro and SS-B/La antibodies increases the risk of neonatal lupus [17-21]. Close monitoring of the pregnancy by ultrasound to observe the unborn child is particularly important for such patients. In addition, treatment of the mother with hydroxychloroquine seems to reduce the risk of cardiac lupus in the child.
Treatment during pregnancy
The basic requirement for a successful pregnancy is good monitoring of disease activity. Women with well-regulated lupus have higher rates of fertility, suffer fewer flare-ups during pregnancy and immediately afterward, are less likely to suffer complications in pregnancy, and give weight to babies with more normal birth weights. Doctors today thus generally recommend planning a pregnancy only after the disease is stable and the medications well adjusted.
Treatment during pregnancy should involve only conventional and extensively tested medications, preferably with only a single substance at the lowest possible dose. A patient requiring treatment for RA during pregnancy could take NSAR, prednisone, sulfasalazine, or hydroxychloroquine. In cases of SLE, steroids are used, as well as primarily anti-malarial medications. If disease activity is high, azathioprine may be given. If a flare-up occurs during pregnancy, NSAR (up to the 32nd week) and steroids may be used. Methotrexate is a folic acid antagonist with teratogenic effects and should preferably be replaced with a safer anti-rheumatic drug before a pregnancy is even planned [22;23;24].
To date there has been little experience with TNF blockers and other biologics in pregnancy. The evaluation of about 1000 individual case reports, clinical studies, retrospective surveys, and records of study results do not indicate a noteworthy increase in risk of malformations when TNF blockers are taken early in pregnancy. Biologics were usually tapered off over the course of the first trimester of pregnancy, so data for the critical phase of late pregnancy is especially sparse. In the second and third trimesters, increased numbers of maternal antibodies cross into the child’s blood stream. In this way, biologics such as TNF antibodies or anti-CD 20 antibodies could also act on the immune system of the child [23;25-27].
A newer British study  compares data from the records of the British Society for Rheumatology Biologics (BSRBR) regarding the use of TNF blockers and methotrexate (MTX) up until the time of conception. Based on the medications used, the pregnancies in the records were divided into four groups: 1, TNF blocker + MTX or other DMARD at conception; 2, only TNF blocker at conception; 3, TNF blocker before conception; and 4, no TNF blocker. During the first trimester of pregnancy, 80 % of the patients tapered off the TNF blocker. No clusters of malformations were observed, though there was an increased rate of miscarriage, particularly in the group taking a combination of drugs. These could be the effect of treatment with MTX or a fundamentally more aggressive case of the disease.
A more recent American study also came to the conclusion that women with an autoimmune disease who take immunosuppressive drugs during the first three months of pregnancy have no increased risk of pregnancy complications .
Thanks to intensive research and new findings regarding the underlying pathomechanisms of rheumatic diseases as well as the effects and safety of DMARDS and biologics, the number of successful pregnancies in patients with rheumatic disease that result in healthy children has increased to 85-90 % in recent years. Through good care from closely cooperating rheumatologists and gynaecologists, women with rheumatic disease who wish to have children definitely have the opportunity for a successful pregnancy, despite the risks.
1. Clowse,M.E., Chakravarty,E., Costenbader,K.H., Chambers,C., and Michaud,K., Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken.) 2012. 64: 668-674.
3. Wallenius,M., Skomsvoll,J.F., Irgens,L.M., Salvesen,K.A., Nordvag,B.Y., Koldingsnes,W., Mikkelsen,K., Kaufmann,C., and Kvien,T.K., Fertility in women with chronic inflammatory arthritides. Rheumatology (Oxford) 2011. 50: 1162-1167.
4. de Man,Y.A., Dolhain,R.J., van de Geijn,F.E., Willemsen,S.P., and Hazes,J.M., Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum 2008. 59: 1241-1248.
6. Wallenius,M., Skomsvoll,J.F., Irgens,L.M., Salvesen,K.A., Koldingsnes,W., Mikkelsen,K., Kaufmann,C., and Kvien,T.K., Postpartum onset of rheumatoid arthritis and other chronic arthritides: results from a patient register linked to a medical birth registry. Ann Rheum Dis 2010. 69: 332-336.
8. Wallenius,M., Skomsvoll,J.F., Irgens,L.M., Salvesen,K.A., Nordvag,B.Y., Koldingsnes,W., Mikkelsen,K., Kaufmann,C., and Kvien,T.K., Pregnancy and delivery in women with chronic inflammatory arthritides with a specific focus on first birth. Arthritis Rheum 2011. 63: 1534-1542.
9. Norgaard,M., Larsson,H., Pedersen,L., Granath,F., Askling,J., Kieler,H., Ekbom,A., Sorensen,H.T., and Stephansson,O., Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med 2010. 268: 329-337.
10. Lin,H.C., Chen,S.F., Lin,H.C., and Chen,Y.H., Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a nationwide population-based study. Ann Rheum Dis 2010. 69: 715-717.
14. Clowse,M.E., Magder,L.S., and Petri,M., The clinical utility of measuring complement and anti-dsDNA antibodies during pregnancy in patients with systemic lupus erythematosus. J Rheumatol 2011. 38: 1012-1016.
15. Tunks,R.D., Clowse,M.E., Miller,S.G., Brancazio,L.R., and Barker,P.C., Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol 2013. 208: 64-67.
16. Ruffatti,A., Tonello,M., Visentin,M.S., Bontadi,A., Hoxha,A., De,C.S., Botta,A., Salvi,S., Nuzzo,M., Rovere-Querini,P., Canti,V., Mosca,M., Mitic,G., Bertero,M.T., Pengo,V., Boffa,M.C., and Tincani,A., Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology (Oxford) 2011. 50: 1684-1689.
17. Izmirly,P.M., Saxena,A., Kim,M.Y., Wang,D., Sahl,S.K., Llanos,C., Friedman,D., and Buyon,J.P., Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus. Circulation 2011. 124: 1927-1935.
18. Capone,C., Buyon,J.P., Friedman,D.M., and Frishman,W.H., Cardiac manifestations of neonatal lupus: a review of autoantibody-associated congenital heart block and its impact in an adult population. Cardiol.Rev 2012. 20: 72-76.
19. Izmirly,P.M., Llanos,C., Lee,L.A., Askanase,A., Kim,M.Y., and Buyon,J.P., Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum 2010. 62: 1153-1157.
20. Izmirly,P.M., Kim,M.Y., Llanos,C., Le,P.U., Guerra,M.M., Askanase,A.D., Salmon,J.E., and Buyon,J.P., Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis 2010. 69: 1827-1830.
22. Fischer-Betz,R., Specker,C., Brinks,R., Aringer,M., and Schneider,M., Low risk of renal flares and negative outcomes in women with lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Rheumatology (Oxford) 2013. 52: 1070-1076.
26. Witt,M., Grunke,M., Proft,F., Baeuerle,M., Aringer,M., Burmester,G., Chehab,G., Fiehn,C., Fischer-Betz,R., Fleck,M., Freivogel,K., Haubitz,M., Kotter,I., Lovric,S., Metzler,C., Rubberth-Roth,A., Schwarting,A., Specker,C., Tony,H.P., Unger,L., Wassenberg,S., Dorner,T., and Schulze-Koops,H., Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) – results from a nationwide cohort in Germany (GRAID). Lupus 2013. 22: 1142-1149.
28. Verstappen,S.M., King,Y., Watson,K.D., Symmons,D.P., and Hyrich,K.L., Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011. 70: 823-826.
29. Cooper,W.O., Cheetham,T.C., Li,D.K., Stein,C.M., Callahan,S.T., Morgan,T.M., Shintani,A.K., Chen,N., Griffin,M.R., and Ray,W.A., Adverse fetal outcomes associated with immunosuppressive medications for chronic immune mediated diseases in pregnancy. Arthritis & Rheumatism 2013. n/a.