Rheumatic Diseases in Women & Children: Current Perspectives Shefali K Sharma, Sujata Sawhney
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SECTION 1
1WOMEN ISSUES IN RHEUMATIC DISEASES
  • 1. Rheumatoid Arthritis and Pregnancy
  • 2. Pregnancy and SLE
  • 3. Lupus Nephritis and Pregnancy
  • 4. Pregnancy in Systemic Sclerosis
  • 5. Antiphospholipid Syndrome in Pregnancy
  • 6. Systemic Vasculitis and Pregnancy
  • 7. Antirheumatic Drugs in Pregnancy
  • 8. Use of Antirheumatic Drugs During Lactation
  • 9. Risk of Children Born to Mothers with Rheumatic Diseases2

Rheumatoid Arthritis and PregnancyCHAPTER 1

Ashok Kumar,
Anil Abrol
 
INTRODUCTION
Rheumatoid arthritis (RA) is a systemic autoimmune disease that leads to destructive arthropathy and inflammation of other structures with an estimated population prevalence of 1%. Since RA is a female-predominant disease (female:male ratio = 3:1), it is worthwhile to understand its effect on pregnancy. Pregnancy is a special situation in which there is a spontaneous improvement in RA disease activity in a substantial proportion of patients. With improvement in the treatment regimens over the last few decades, more women with RA can now consider childbearing than earlier. This chapter reviews the effect of RA on fertility, effects of disease activity on pregnancy outcomes and possible mechanisms mediating these effects.
 
FERTILITY IN RHEUMATOID ARTHRITIS
Many women are diagnosed with RA around the time of marriage or when they are planning to start a family. Women with RA tend to take longer to conceive, have fewer children or are more likely to be nulliparous. However, there is no consensus regarding RA-induced infertility. A recent study confirmed the notion that time taken for conception is slightly longer in women with RA, also indicating a slight reduction in fecundity (probability of achieving viable pregnancy in a single menstrual cycle).1 Though prior studies demonstrated that influences on childbearing decisions are rather by choice than due to infertility,1–4 a recent study depicted that infertility played a significant role beyond patient's choice.5 This may be due to different mechanisms viz, physical, psychological, hormonal, immunological or medical treatment related. A high degree of concern about genetic transmission of disease to their offsprings and a physical handicap in care giving capacities has further led to decrease in parity. Many disease-modifying antirheumatic drugs (DMARDs) 4have been associated with teratogenic effects on fetus6 while a significant correlation has been found between nonsteroidal anti-inflammatory drugs (NSAIDs) and reversible infertility.7 Ameliorating effects of estrogen containing oral contraceptives on RA disease activity has propagated their use, further contributing to low birth rates. A single small prospective study has suggested a decreased ovulatory function8 in RA which needs a further confirmation by larger studies. A recent Norwegian population-based study stated more use of assisted reproduction techniques in women with RA as compared to age-matched healthy women.9
 
EFFECTS OF PREGNANCY ON RHEUMATOID ARTHRITIS
 
Pregnancy and RA Disease Activity
Alterations in the immune system caused by pregnancy possibly change the course of RA. Ever since the first publication by Hench,10 it has been known that RA disease activity decreases in 75–90% of patients during pregnancy3,11–13 followed by a postpartum flare. The higher figures come from rather small and retrospective studies often relying on patient recall and sometimes lacking validated tools for assessing disease activity. Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study by de Man et al. evaluated disease activity using changes in DAS-28-3 (CRP). They showed significant decrease in activity scores during pregnancy (39% patients) and deterioration postpartum (38% patients), although less than previously described. This can be explained by use of more objective tools for measuring disease activity and better preconception disease control over the decades leaving less room for pregnancy associated improvement.14 Limited data available in the literature suggests a marked decrease in extra-articular manifestations like rheumatoid nodules in pregnancy.15
 
Postpartum Period and RA Disease Activity
There has been substantial evidence of worsening of RA in postpartum period. A recent study emerging from Norwegian registry demonstrated an increase in incidence of RA during first 24 months postpartum.16 Differences in relative glucocorticoid (GC) sensitivity, determined by GC receptor polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients though, not influencing the course of the disease per se.17
Interestingly, multiparous females have been shown to have improved long-term disease outcome in RA with less erosions and better functional level.18 This beneficial effect of parity diminishes with time.19 A recent study revealed a significantly lower risk of RA in multiparous women, which correlated inversely with time elapsed since last delivery. HLA-disparate fetal microchimerism can persist many years after a birth and could confer temporary protection against RA. A possibility that pregnancy might provide vaccine-like temporary protection against RA merits further investigation.20
5
 
Breastfeeding and RA Disease Activity
A review of literature on effect of breastfeeding on RA disease activity revealed contradictory results. Early evidence suggested that RA risk was increased by breastfeeding, especially after the first pregnancy. This may be possibly due to a surge in the proinflammatory hormone prolactin which unmasks latent RA in a susceptible individual.21 Another small study found that longer the duration of breastfeeding, more was the risk of developing RA, especially among individuals seropositive for anti-citrullinated protein antibody (ACPA) or IgM-RF or carrying the PTPN22 1858T variant.22 Prospective studies, however, depicted a dose-dependent inverse association with duration of breastfeeding and RA risk.23,24 From an RA perspective, if the first pregnancy passes without postpartum flare, then the individual may breastfeed longer. The same pattern continues in subsequent pregnancies. Thus, the protection afforded by longer duration of breastfeeding may, in part, be an example of elimination of susceptibles.25
 
POSSIBLE MECHANISMS OF EFFECTS ON DISEASE ACTIVITY
 
During Pregnancy
The reasons behind the beneficial effects of pregnancy on RA activity remain largely unknown. Combined effects of pregnancy-related hormonal and immunological alterations are considered as the possible explanation:
  1. Clinical improvement in RA does not show any correlation with rheumatoid factor (RF) and ACPA levels, although patients with a negative RF and ACPA are more likely to improve during pregnancy.26
  2. Cell-mediated immunity:
    1. Reduced cell-mediated immunity.
    2. Shift towards a TH2-dominant immune response.27
    3. Reduced NK-cell activity (HLA-C, HLA-E, HLA-G expression on trophoblast cells).
    4. Elevated levels of anti-inflammatory cytokines such as interleukin-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor-alpha receptors (sTNFRs).28
    5. Decreased neutrophil respiratory burst.29
  3. Humoral immunity:
    1. Increased galactosylation of serum IgG is thought to diminish its antigenicity and the proinflammatory properties of Immunoglobulin autoantibodies like RF,30 but still the question remains, whether it is a mere epiphenomenon or a true remission-inducing factor.31
    2. An elevated level of serum alpha-2 pregnancy-associated globulin (α2-PAG), though its value in disease activity is limited.32
  4. 6Hormonal changes:
    1. Increase in progesterone level leads to negative immunomodulation and thymic involution.33
    2. Combined effect of increased levels of cortisol, estrogen and vitamin D has been implicated in lowering IL-12 and TNF-α.34
    3. Fetal human chorionic gonadotropin (hCG) recruits regulatory T cells (TReg) which protect fetus by inhibiting activation of effector T cells by expressing inhibitory cytokines IL-10 and TGF-β. Number of TReg in pregnant women with RA correlates inversely with disease activity in 3rd trimester and postpartum.35
    4. Higher the degree of human leukocyte antigen (HLA) disparity between mother and fetus, more are the chances of RA to remit.36
 
Postpartum Period
  1. Elevated levels of prolactin which is a proinflammatory hormone.37,38
  2. A decrease in levels of anti-inflammatory steroids.
  3. Changes in neuroendocrine axis.
  4. A change from a Th2 to Th1 cytokine profile.
 
PREGNANCY OUTCOMES IN RHEUMATOID ARTHRITIS
A well-controlled RA has a pregnancy outcome at par with general obstetric population. Earlier observations had shown no changes in feto-maternal outcomes in RA in the absence of teratogenic medications such as methotrexate, leflunomide, etc. However, more recent studies have pointed towards unfavorable outcomes. A Dutch PARA study showed an independent relationship between low birth weight and active 3rd trimester disease and indirectly with prednisolone usage.39 Preeclampsia and cesarean section rates are higher in RA patients. Altogether, data available till date suggests a moderate risk of prematurity, low birth weight and a slight decrease in fecundity in patients with highly active RA, which can be otherwise mitigated by achieving a good control of disease, especially in 3rd trimester.39,40
 
Ways to Improve Pregnancy Outcomes in Rheumatoid Arthritis
To improve pregnancy outcomes in RA, it is necessary to achieve a good control of the disease both before conception and intrapartum. A systematic preconception counseling regarding medications use and genetic transmission related issues is likely to pay high dividends. Monitoring disease activity in pregnancy can be difficult, as the markers of systemic inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] can be misleading.14 ESR values are less reliable than CRP during pregnancy. DAS28 (CRP) without assessment of global health is a preferred tool for measuring RA disease activity in pregnant patients.41,42 Constitutional symptoms due 7to pregnancy per se may be misinterpreted. Medication safety issues will be discussed in detail in the following chapters.
 
CONCLUSION
Most patients with RA improve during pregnancy and develop flares in the postpartum period. Combined effects of pregnancy-related hormonal and immunological alterations are considered as the possible mechanism. Interestingly, multiparity has a vaccine-like effect on RA, reducing the risk of the disease. RA should be well-controlled before conception, as well as during pregnancy, to ensure a good outcome. Preconception counseling, therefore, has a crucial role in this regard.
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