Rheumatic diseases (RDs) occur preferentially in women, often during the childbearing age. The interaction of pregnancy and the RD is varied, ranging from spontaneous improvement to aggravation of disease symptoms or life-threatening flares. Risks for the mother with RD and the child differ in regard to the presence of organ manifestations, organ damage, disease activity, presence of specific autoantibodies, and therapy. Pregnancy complications comprise hypertension, preeclampsia, premature delivery, and side effects of therapy. Adverse pregnancy outcomes include recurrent miscarriage, intrauterine growth restriction, and fetal demise, and they are frequently encountered in RD with organ manifestations and harmful autoantibodies. Because of the difference in the prevalence of RDs, knowledge on the gestational course of disease and pregnancy outcome is limited to the fairly common RDs such as rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Pregnancies in RD are connected with increased risks for mother and child and need interdisciplinary care and management.
Highlights
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Rheumatic diseases differ in regard to pregnancy outcome.
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Adverse outcomes relate to disease pathophysiology.
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Disturbance of placental function is key for pregnancy complications.
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Planning and interdisciplinary management support successful pregnancy outcomes.
Introduction
Rheumatic diseases (RDs) differ markedly in regard to maternal and fetal risks during pregnancy. Important factors associated with risk are the type of disease, disease activity at conception and during pregnancy, organ involvement, presence of autoantibodies, comorbidities, and therapy. As a general rule, the extent of the immuno-inflammatory process; the involvement of vital internal organs such as kidney, lung, and heart; and immunosuppressive therapy contribute to pregnancy complications and adverse outcomes. The physiological adaption of the body to pregnancy can aggravate or unmask organ dysfunction already present in the mother.
Diseases with no or few organ manifestations and predominant joint involvement are the ones that carry few risks of pregnancy complications and child outcome . Rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and the spondyloarthritides (SpA) belong to the group with few organ manifestations ( Table 1 ) . By contrast, the connective tissue diseases (CTDs), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis (SSc), inflammatory myopathies, and vasculitis are associated with multiple autoantibodies, multiorgan involvement, and more aggressive therapy ( Table 1 ). The risk of adverse pregnancy outcomes is significantly increased in these more severe CTDs . B cell hyperactivity with abundant production of autoantibodies is seldom found in the diseases characterized predominantly by joint inflammation, but is a hallmark of SLE, SSc, and vasculitis. Autoantibodies such as antiphospholipid (aPL) antibodies and anti-Ro and anti-La can exert negative effects on pregnancy outcome and child health .
| Disease | Autoantibodies | Frequent extra-articular organ involvement |
|---|---|---|
| Rheumatoid arthritis | Rheumatoid factor (RF), citrullinated protein antibodies, antiphospholipid antibodies | Present in about 30% of patients: lung, heart, serositis, vasculature |
| Ankylosing spondylitis | None a | Uveitis |
| Psoriatic arthritis | None a | Skin psoriasis |
| Juvenile idiopathic arthritis | RF and antinuclear antibodies in some subgroups | Uveitis, systemic features in Morbus Still |
| Sjogren’s syndrome | ANA, RF, anti-Ro, anti-La | Xerophthalmia, xerostomia, parotid gland enlargement, lung, kidney, gastrointestinal tract, lymphadenopathy |
| Antiphospholipid syndrome | anti-cardiolipin antibodies, β2-glycoprotein I antibodies, lupus anticoagulant | Skin, vasculature, lung, heart, kidney, CNS, placenta |
| Systemic lupus erythematosus | ANA, anti-dsDNA, anti-Smith, anti-ribonucleoprotein (RNP), anti-Ro, anti-La, anti-phospholipid antibodies | CNS, skin, lung, heart, kidney, vasculature, muscles, hematopoietic system |
| Systemic sclerosis (diffuse and limited form) | ANA, Scl 70, anti-centromer antibodies, RNA polymerase types II and III, | Skin, gastrointestinal tract, lung, heart, kidney, vasculature |
| Vasculitis (granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome), microscopic polyangiitis | Anti-neutrophil cytoplasmic antibodies (ANCAs) | Vasculature, upper airways, skin, lungs, kidney, peripheral nervous system, eye, CNS |
a Autoantibodies can occur in 1–5% of the patients, but are not a characteristic of the disease.
Another difference among RDs is the propensity to flare during pregnancy. Two types of flares have to be considered: an aggravation of joint inflammation (arthritis) and a relapse or new onset of inflammation in internal organs. Aggravation of arthritis is a frequent problem in RA, JIA, and SpA, and the second is a serious complication of SLE, APS, SSc, and vasculitis . Inflammation in only one, few, or in multiple joints creates pain, stiffness, and impaired function, but can be experienced as more disabling than a silent organ manifestation . The burden of systemic inflammation depends on the extent of arthritis or of the number of organs involved. Both acute arthritis and inflammation in internal organs during pregnancy require treatment, although affection of internal organs often needs more aggressive therapy due to the more severe consequences of organ damage.
Disease course during pregnancy
RDs show no uniform response to pregnancy: some ameliorate, others remain unchanged, and several RDs aggravate . The response of disease to the hormonal, immunological, and biochemical alterations of pregnancy reflects the pathophysiology of the different RDs. RA is the RD that improves spontaneously during pregnancy in a majority of patients , at least in those who have no autoantibodies like rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) . Spontaneous improvement starts often already in the first trimester with a reduction of pain, stiffness, and joint swelling and reaches a maximum in the third trimester . RA patients without RF or ACPA will ameliorate in 75% of cases, whereas patients positive for RF and ACPA only have a 40% chance to improve during pregnancy . Polyarticular JIA and psoriatic arthritis (PA) also show a tendency of spontaneous gestational improvement . By contrast, inflammatory arthritides with few joints involved or with inflammation of the spine like ankylosing spondylitis (AS) do not show improvement during pregnancy. Most women with AS remain active and need control of pain and stiffness in the spine throughout pregnancy .
SLE is the prototype of a multiorgan disease with abundant autoantibody production. The flare rate during pregnancy has differed in several case–control studies from no difference in pregnant and nonpregnant patients to an increased propensity of flare during pregnancy . Definition of a flare and type of patients included influence the flare rate observed . In general, there is agreement that SLE is active at some stage during pregnancy in about 50% of the patients though 60–70% of lupus women do experience mild to moderate disease symptoms, most often in the skin, the joints, and in the hematopoietic system. Severe organ flares in the kidney, lung, or CNS are limited to 11–25% of pregnancies . Active SLE during pregnancy increases the rate of negative outcomes two-to fourfold .
SSc, inflammatory myopathies, and vasculitis are rare diseases. Published experience of their course during pregnancy and pregnancy outcome is quite limited and consists frequently of retrospective uncontrolled studies and case reports . General statements on their interaction with pregnancy are difficult to make. However, it appears that the type and extent of organ involvement as well as disease activity are the crucial factors for pregnancy outcome .
Disease course during pregnancy
RDs show no uniform response to pregnancy: some ameliorate, others remain unchanged, and several RDs aggravate . The response of disease to the hormonal, immunological, and biochemical alterations of pregnancy reflects the pathophysiology of the different RDs. RA is the RD that improves spontaneously during pregnancy in a majority of patients , at least in those who have no autoantibodies like rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) . Spontaneous improvement starts often already in the first trimester with a reduction of pain, stiffness, and joint swelling and reaches a maximum in the third trimester . RA patients without RF or ACPA will ameliorate in 75% of cases, whereas patients positive for RF and ACPA only have a 40% chance to improve during pregnancy . Polyarticular JIA and psoriatic arthritis (PA) also show a tendency of spontaneous gestational improvement . By contrast, inflammatory arthritides with few joints involved or with inflammation of the spine like ankylosing spondylitis (AS) do not show improvement during pregnancy. Most women with AS remain active and need control of pain and stiffness in the spine throughout pregnancy .
SLE is the prototype of a multiorgan disease with abundant autoantibody production. The flare rate during pregnancy has differed in several case–control studies from no difference in pregnant and nonpregnant patients to an increased propensity of flare during pregnancy . Definition of a flare and type of patients included influence the flare rate observed . In general, there is agreement that SLE is active at some stage during pregnancy in about 50% of the patients though 60–70% of lupus women do experience mild to moderate disease symptoms, most often in the skin, the joints, and in the hematopoietic system. Severe organ flares in the kidney, lung, or CNS are limited to 11–25% of pregnancies . Active SLE during pregnancy increases the rate of negative outcomes two-to fourfold .
SSc, inflammatory myopathies, and vasculitis are rare diseases. Published experience of their course during pregnancy and pregnancy outcome is quite limited and consists frequently of retrospective uncontrolled studies and case reports . General statements on their interaction with pregnancy are difficult to make. However, it appears that the type and extent of organ involvement as well as disease activity are the crucial factors for pregnancy outcome .
Pregnancy outcome
Women with RD in general have been found to have higher risks for adverse outcomes such as pregnancy loss, preeclampsia, preterm delivery, cesarean section (CS), and small for gestational age (SGA) infants . As expected, the pathophysiology of the underlying disease, presence of certain autoantibodies, disease activity during pregnancy, and type of therapy influence the rate of adverse outcomes.
Among the inflammatory arthritides, pregnancy outcome has been most extensively studied in RA . The rate of adverse outcomes reported in RA varies considerably and reflects the difference in study design, patient populations, access to health care during pregnancy, pharmacotherapy, and comorbidities in RA patients. A population-based study in Norway with a specific focus on the first birth examined possible associations between chronic inflammatory arthritides (CIA) and pregnancy outcomes with separate analyses of first and subsequent births before and after diagnosis . Linkage of data from the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) Registry and the Medical Birth Registry of Norway (MBRN) enabled a comparison of pregnancy outcomes in CIA and non-CIA women. Excess risks were related to the first birth in women diagnosed with CIA. No increased risk of preeclampsia was detected. Prospective studies including RA women with well-controlled disease and regular follow-up during pregnancy found that the pregnancy outcome was similar to healthy women in patients entering pregnancy with low disease activity and limited drug therapy .
Pregnancy loss
The incidence of abortions and stillbirths is significantly increased in patients with SLE, APS, and vasculitis, reflecting the presence of harmful autoantibodies, widespread organ manifestations, and organ damage . The high rate of pregnancy losses is typical for APS within the fetal period. In SLE, the rate of pregnancy loss has been found in the range of 11–29%, and it is 1.5–2.5 times more prevalent than in the normal population . Active lupus nephritis, proteinuria, hypertension, previous history of fetal death, and the presence of aPL have shown to be predictive factors for fetal loss in lupus pregnancies . A study of 265 pregnancies found that active SLE in the 3 months prior to conception corresponded with a fourfold increase in pregnancy loss . The rate of stillbirth is increased in both SLE and APS .
Premature delivery
The rate of delivery <37 weeks gestation is higher in patients with RD than in healthy women. Preterm delivery is associated with lung immaturity, with delayed development, and impaired long-term outcomes for children . Early preterm birth (<30 weeks gestation) often leads to prolonged hospitalization with multiple short- and long-term complications. Several studies have reported a 1.2–1.8 increased risk of preterm delivery in patients with inflammatory arthritides (mostly RA), without relating this to birth order . In the Norwegian population-based study, the risks of preterm delivery and SGA children were higher for firstborn children in mothers with CIA compared with references. A recent retrospective study of 46 RA pregnancies found a high rate (28%) of preterm deliveries; however, no analysis of indications or complications leading to preterm delivery was given .
Rates of preterm birth are particularly high in SLE, APS, and SSc . In women with SLE, preterm deliveries are often induced for complications such as lupus nephritis, renal insufficiency, hypertension, preeclampsia, premature rupture of the membranes, and fetal compromise . A key predictor for preterm delivery is lupus activity during pregnancy, even in patients with quiescent SLE before conception or with mild to moderate activity in pregnancy . A meta-analysis found that the rate of preterm birth was 39.4% in women with lupu s nephritis . Other risk factors are treatment with a high dose (>20–15 mg) of corticosteroids .
In addition, patients with SSc have a significantly increased rate of preterm birth possibly related to placental insufficiency due to vasculopathy of the placenta .
Many studies have not analyzed the reason for delivery <37 weeks of gestation or separated emergency preterm delivery from delivery for other reasons. Sometimes, preterm delivery is induced because of anxiety in the patient or because the obstetricians fear complications should parturition occur spontaneously. Accordingly, the rate of emergency premature delivery due to maternal complications or due to fetal distress may be lower than the actual one reported. The wish for a delivery under controlled conditions can be a strong motive for preterm delivery.
Cesarean section
The rate of CS is increased in all RDs . Several population-based studies from different geographic areas have found a 1.5–2.0 increased risk of CS in patients with RA . The Norwegian study has examined both acute and elective CS in CIA separately . In this study, acute CS was not observed to be more frequent in patients than references, but the rate of elective CS was doubled among patients in both first and subsequent pregnancies. Placental dysfunction, cephalopelvic disproportion, and combined causes constituted each one-third of the indications . However, iatrogenic reasons or the wish of the patient for surgical delivery may play a role for choosing elective CS in women with RD.
In the Norwegian population-based study, women with AS had the highest occurrence of elective CS (25%) among the different diagnostic groups , a finding also confirmed by previous studies . Inflammation or ankylosis of the sacroiliac joints is not a mechanical hindrance for the progression of parturition nor is spinal disease. Anesthesiologists often fear that neuraxial anesthesia is difficult to establish in patients with AS because of ankylosis in the lumbar spine. However, ankylosis of the lumbar spine is rare in female AS patients and occurs only after three to four decades of disease duration .
Neonatal and perinatal outcome
Perinatal morbidity and mortality have been found increased in RDs . In the Norwegian population-based study, the perinatal mortality rate of firstborn children of mothers diagnosed with inflammatory arthritis was three times higher in children of patients than in references. Perinatal mortality is also increased in children born of mothers with SLE (5–20%) or APS . In the APS, a rate of up to 54% perinatal death has been observed mainly due to severe preeclampsia or the HELLP (hemolysis, elevated liver enzymes, low platelets, and proteinuria) syndrome with resulting extreme prematurity .
The Norwegian population-based study showed small, but statistically significant, lower mean birth weight in the firstborn, but not later children of women with RD compared to references. Several studies of RA pregnancies found birth weight within the normal range, but lower than in healthy women, and even lower in infants of RA mothers with high disease activity or on prolonged therapy with corticosteroids . In RA pregnancies with well-controlled disease activity and with no or minimal use of prednisone, no increase in prematurity or SGA infants has been found . The rate of congenital malformations in children of patients with RD is not increased, except for birth defects arising from first-trimester exposure to teratogenic drugs such as methotrexate and cyclophosphamide ( Table 2 ) .
| Disease | Flare in pregnancy | Risk of pregnancy complication | Risk of adverse child outcome |
|---|---|---|---|
| Rheumatoid arthritis | 10–25% | Rare, associated with active disease and use of corticosteroids | Rare, associated with active disease and use of corticosteroids |
| Ankylosing spondylitis | 50% | Rare | Not increased |
| Psoriatic arthritis | 20% | Few studies, no conclusive data | Few studies, no conclusive data |
| Juvenile idiopathic arthritis | 30–40% | Few studies, no conclusive data | Few studies, no conclusive data |
| Antiphospholipid syndrome | No flare, but risks for adverse outcomes increased | Thrombosis, preeclampsia, HELLP, premature delivery | Early and late miscarriage, IUGR, stillbirth, prematurity |
| SLE | 27–65% | Hypertension, preeclampsia, premature delivery | Miscarriage, IUGR, still birth, prematurity, neonatal lupus syndromes |
| Systemic sclerosis | No flare, symptoms largely unchanged during pregnancy | Premature delivery | IUGR, prematurity |
Autoantibodies impairing pregnancy outcome
Several RDs are associated with the abundant production of autoantibodies. The APS is the classical example of pathology and clinical manifestations connected with the presence of autoantibodies. APS is characterized by thromboembolic events and pregnancy morbidity as major manifestations at the presence of aPL . The most prominent antibodies detected in the APS are lupus anticoagulant (LAC), anti-cardiolipin (aCL), and anti-beta 2 glycoprotein I (aβ 2 GP1). Several other antibodies including anti-annexin V, anti-phosphatidyl serine, and anti-prothrombin have been detected, but are not used for routine testing. Until now, no autoantibody has been found to be pathognomic for pregnancy complications. However, several studies have shown that high titers of aPL, presence of LAC, and triple positivity (aCL + LAC + aβ 2 GP1) are associated with a high risk of adverse pregnancy outcomes . aPL are detected not only in the APS and in SLE but also in other RDs as well as in infections.
The pregnancy complications of the APS include pregnancy loss, intrauterine growth restriction (IUGR), preeclamptic toxemia (PET), HELLP syndrome, placental abruption, stillbirth, and premature delivery. PET has been reported to occur in about one-third of patients with APS, often with early onset before 34 weeks of gestation . The risk of HELLP is increased in APS with a frequency of 0.66–10.6% reported, and often manifesting in the second trimester . Both HELLP and PET occur earlier in APS pregnancy than in the general obstetric population.
The rate of IUGR is high ranging from 15% to 43% in the APS indicating placental insufficiency . However, the pathogenesis of placental insufficiency is only partly clarified. Histological studies of placentas from patients with APS have shown varying patterns with necrosis, infarction, intravascular fibrin deposition, syncytial knot formation, fibrosis, and sometimes inflammatory infiltrates . However, these histological abnormalities are nonspecific and no specific placental lesions or patterns of abnormalities characteristic of the APS have been detected. Furthermore, histological findings in the placenta and pregnancy outcome are often unrelated .
The transplacental transfer of maternal autoantibodies to 52-kd SSA/Ro, 60-kd SSA/Ro, or SSB/La ribonucleoproteins from the beginning of the second trimester can lead to neonatal lupus syndromes including congenital heart block (CHB) . SSA and/or SSB antibodies can occur in all RDs as well as in healthy mothers. In susceptible children, the maternal SSA and/or SSB antibodies can damage the conduction system of the fetal heart, with the most vulnerable period being between week 18 and week 26 of gestation . Of children born from mothers with SSA and/or SSB antibodies, 2–5% develop CHB . The fetal heart rate must therefore be monitored regularly between week 18 and 28 in pregnant women with significantly elevated levels of SSA and/or SSB antibodies .
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