Fertility and pregnancy in systemic sclerosis and other autoimmune rheumatic diseases
Vijay K R Rao
Department of Rheumatology, Manipal Hospitals, Bengaluru, Karnataka, India
Department of Rheumatology, Manipal Hospitals, Bengaluru, Karnataka
Autoimmune rheumatic diseases usually occur in women of childbearing age. In the past, pregnancy in women with autoimmune rheumatic diseases was not considered safe and was discouraged because gestation could worsen maternal disease and vice versa, and the disease could negatively affect the gestational outcome. However, women with rheumatic diseases often wish to have children even when functional disability is present. The great improvement in the systematic approach to pregnancy over the past few decades has allowed an increasing number of affected women to fulfill their family plan. Women should be informed about potential risks related to their disease and also should be reassured that a good pregnancy outcome is possible if conception occurs when they are in a stable remission state, teratogenic medications have been properly withdrawn, and immunosuppressant drugs that are safe in pregnancy have been maintained to prevent disease flare. The interaction of pregnancy and the rheumatic diseases can vary from spontaneous improvement to flare of disease symptoms. Rheumatic diseases differ in regard to the occurrence of complications during pregnancy and to pregnancy outcome. This review describes the maternal course of systemic sclerosis, ankylosing spondylitis, polymyositis and dermatomyositis during pregnancy, fetal outcome, and therapy during pregnancy and postpartum.
Keywords: Ankylosing spondylitis, dermatomyositis, fertility, polymyositis, pregnancy, scleroderma, systemic sclerosis
Rao VK. Fertility and pregnancy in systemic sclerosis and other autoimmune rheumatic diseases. Indian J Rheumatol 2016;11, Suppl S2:150-5
Rao VK. Fertility and pregnancy in systemic sclerosis and other autoimmune rheumatic diseases. Indian J Rheumatol [serial online] 2016 [cited 2022 Jan 18];11, Suppl S2:150-5. Available from: https://www.indianjrheumatol.com/text.asp?2016/11/6/150/194550
Autoimmune rheumatic disease covers a spectrum of conditions, including systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), rheumatoid arthritis (RA), other inflammatory arthropathies/spondyloarthropathies, systemic sclerosis (SSc), systemic vasculitides, and other connective tissue diseases. In the past, pregnancy was not considered safe in women with multisystem rheumatic diseases. This review shows that with good disease control, careful planning, and combined management, delivery of healthy babies is often possible.
Immunology of Pregnancy
Pregnancy induces hormonal changes in the maternal body, which are necessary for the support of pregnancy and fetal survival. As the pregnancy advances, circulating plasma levels of cortisol, estrogens, and progesterone steadily rise. [1] In addition, immunoregulatory factors secreted by the placenta suppress T-cell proliferation and induce tolerance in maternal T-cells. [2] Pregnancy does not result in a general state of impaired immunity. The maternal defense mechanisms remain intact with normal responses to active and passive immunization but tolerance to fetal antigens.
Cytokines and the TH1/TH2 Immune Response in Pregnancy and Postpartum
Successful pregnancy is largely dependent on a TH2 cytokine profile, whereas spontaneous abortion shows a TH1 cytokine pattern. [3] Evidence for this shift of the TH response is strongest at the maternal-fetal interface. However, a modulation adapted to the stage of pregnancy takes place and a persistent domination of a TH2 cytokine pattern is not seen throughout pregnancy. Studies have shown an increase of anti-inflammatory cytokines in pregnancy that are able to induce tolerance. [1] The increase of regulatory T-cells suppresses the proliferation of interferon gamma and interleukin-12 (IL-12) producing effector T-cells and promotes the secretion of IL-10, IL-4, and transforming growth factor-beta. [4] The interaction of paternal HLA antigens with maternal peripheral blood mononuclear cells stimulates the production of IL-4, thereby promoting a TH2 response. [5] Cortisol, catecholamines, and other factors decrease postpartum leading to an increase of pro-inflammatory cytokines and more vigorous B-cell responses causing an immunological rebound.
Systemic Sclerosis
SSc is a rare autoimmune disease causing cutaneous, musculoskeletal, cardiovascular, pulmonary, gastrointestinal, and renal manifestations. Etiology of SSc is largely unknown. SSc has an incidence of 2-10 cases per million and prevalence of 150-300 cases per million worldwide. It is common in women aged 40-60 years, with a female to male ratio of 4-10:1. [6] The most common causes of morbidity and mortality from SSc are interstitial lung disease and pulmonary hypertension.
Pregnancy and systemic sclerosis
Despite the fact that pregnancy in SSc is a high-risk pregnancy, successful outcomes with lesser risk of serious complications may be possible if the patient receives combined care of the obstetrician and the rheumatologist, an appropriate time for pregnancy is chosen, and close obstetric monitoring is performed. [7]
Pregnancy should be considered only after the assessment of disease subtype (diffuse or limited), categorization of the stage of disease (early or late), and assessment of the extent of internal organ involvement. Pregnancy should be delayed in patients with early disease (<4 years), diffuse subtype, or anti-topoisomerase 1 or anti-RNA polymerase 3 antibodies due to higher associated obstetric risk. [7] Complications such as hypertension, renal failure, pulmonary hypertension, interstitial lung disease, or heart failure are seen in the later half of pregnancy. [8]
Fertility and systemic sclerosis
Studies show that the rate of infertility in patients with SSc is 15%, while the rate of successful pregnancies in patients evaluated for infertility is 37% for patients with SSc, 40% for patients with RA, and 43% for healthy women. Hence, there are no significant differences in the frequency of infertility or the rate of successful pregnancy in SSc before or after disease onset. [9] However, sex life could be affected due to vascular lung disease, skin and physical limitations, as well as changes in the appearance and the emotional effects of the disease, thus affecting the possibility of conception. The main symptoms reported by patients affecting their sex life were fatigue, muscle/joint pain, vaginal dryness, dyspareunia, Raynaud's phenomenon, sore hands, digital ulcers, dyspnea, and chest pain. [10] In addition, there could be a coexisting secondary antiphospholipid antibody syndrome (APS) in 50% of patients with SSc and ulcers of the lower limbs, indicating the association of SSc and APS as an additional cause for recurrent pregnancy loss in these patients. [11]
Effects of pregnancy on systemic sclerosis
Several studies have shown that there are no significant changes in the disease during pregnancy. A prospective study has shown that disease was stable in 60% of the patients, improvement in 20%, and worsening in 20% patients. Raynaud's phenomenon in particular can improve, but other symptoms such as reflux, skin thickening, and arthritis can worsen. [12] In this series, three cases of renal crisis occurred during pregnancy.
This same study showed that in the postpartum period, one-third had a flare in Raynaud's phenomenon, arthritis, skin thickening. The 10-year survival of SSc patients was similar with and without pregnancy. [12]
Raynaud's phenomenon and vascular disease improve during pregnancy, presumably due to vasodilation and increased cardiac output during the second half of pregnancy. [13] However, postpartum, there may be a flare and hence treatment needs to be restarted early in those with previous ulcers or amputations.
Scleroderma (cutaneous manifestation) is usually stable during pregnancy. However, worsening has been seen in those who discontinue treatment. [12]
Joint pains and arthritis are not frequent in SSc. Nausea, vomiting, and reflux are common in SSc and often get worse in pregnancy. Intestinal dysmotility and bacterial overgrowth can threaten the life of the mother and the baby, so its management should be continued throughout pregnancy. [12],[13]
There is no decline in lung function with mild fibrosis (forced vital capacity [FVC] >65%). [12] In mild cases of pulmonary fibrosis, there are reports of successful outcomes; however, in severe pulmonary fibrosis (FVC <65%), there could be increased risk of preterm delivery and abortions. In addition, dyspnea increases during the third trimester of pregnancy.
Pulmonary arterial hypertension (PAH) gets worse during and after pregnancy. [13] PAH in SSc is associated with the limited cutaneous form, presence of anti-centromere antibodies, anti-TH/To, and anti-U3 RNP. Pregnancy is not recommended in the presence of PAH because it leads to severe hemodynamic complications as the pulmonary arterioles are not able to handle the increased blood volume and cardiac output seen during pregnancy. A systematic review of all cases of pregnant women with idiopathic PAH, PAH associated with congenital heart disease, and other types of PAH showed that mortality in idiopathic PAH was 17% in idiopathic PAH and 33% in other forms of PAH. The mortality risk was highest during labor and within the 1 st month after delivery. [14] It is also shown that these patients have an increased risk of hospitalization and hypertensive disorders of pregnancy. [15] Hence, patients with SSc and PAH should avoid conception and can be offered for elective termination of pregnancy.
Renal crisis is seen in 5%-10% of patients and is characterized by acute, refractory hypertension, progressive proteinuria, and acute renal failure associated with microangiopathic changes on the biopsy, with the appearance of "onion skin" lesions of the renal arteries associated with endothelial proliferation. [16],[17] It is seen in diffuse cutaneous SSc of rapid evolution in the first 5 years from the onset of symptoms, with the presence of anti-topoisomerase 1 or anti-RNA polymerase 3 antibodies and previous exposure to corticosteroids at doses equal to or >15 mg/day. [7],[8]
One should be vigilant for any possible development of renal crisis. Serum creatinine should be monitored as is blood count to look for microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. In addition, liver function tests should be done to rule out HELLP syndrome and urinalysis to look for proteinuria.
In case of normotensive renal crisis, it is important to rule out thrombotic thrombocytopenic purpura (TTP), in which MAHA, thrombocytopenia, and kidney failure are prominent manifestations. It may be useful to measure the plasma levels of ADAMTS13 since its function is decreased (<10%) or absent in most of TTP patients while normal in patients with SSc and renal crisis. [16]
Another important differential diagnosis to rule out is preeclampsia and eclampsia in which there is hypertension with proteinuria, edema, and raised uric acid. In diffuse SSc (DSSc), pregnancy should be advised 3-5 years after the onset of symptoms and after the disease is stable for at least 6 months. This is because the greatest risk of developing renal crisis is in early disease, rapidly progressive forms, and/or DSSc. [12]
Effects of systemic sclerosis on pregnancy
Spontaneous abortion is reported in 15% of patients after the onset of the disease, but the incidence of abortions in SSc is not higher than the general population or patients with RA. [9]
Placental abnormalities seen in SSc [18] are decidual vasculopathy with stromal fibrosis and chronic infarction of chorionic villi, placental mesenchymal dysplasia, foamy degeneration of endothelial cells with vascular obstruction, foci with decreased vasculature, fibrinoid deposit material, chorioamnionitis, and accelerated placental maturation, which may cause PIH, preterm delivery, fetal growth retardation, and intrauterine growth restriction (IUGR). [6]
A prospective study of 91 pregnancies which occurred to 59 women showed that preterm births occur in 29% SSc pregnancies. [12] However, it appears that the risk of preterm delivery is not significantly higher in SSc when compared to RA or healthy women. [12] Therefore, although preterm births do occur in SSc pregnancies this might be secondary to chronic disease rather than the effect of SSc per se.
Development of hypertension during pregnancy could be due to scleroderma renal crisis, or preeclampsia or an overlap of another like SLE with renal involvement. In such instances, measurement of plasma renin levels can differentiate scleroderma renal crisis from preeclampsia. The serum renin level varies from low to normal in preeclampsia while in SSc renal crisis the plasma renin levels are elevated because of renal cortical ischemia.
Effects on fetus
There is an increase in the frequency of low birth weight babies in pregnancies after SSc onset when compared to a pregnancy before SSc onset (11% vs. 5%, odds ratio 2.462). This is probably due to IUGR during fetal development secondary to vascular disease in SSc. There is no significant increase of stillbirth compared with healthy controls (4% vs. 1.4%-2%). [8],[9],[12]
The presence of anti-Ro/SSA and anti-La/SSB antibodies in the mother has been associated with the development of complete heart block in the fetus and newborn. The prevalence of these antibodies is of 12%-37% for anti-Ro and 4% for anti-La antibodies in SSc. [19] Complete heart block develops in 1%-2% of pregnancies in patients with these antibodies, but the frequency is about 20% with recurrent pregnancies. Hence, weekly fetal heart rate monitoring is recommended in such mothers from 16 weeks onward. [20]
Prepregnancy planning
Detailed assessment of the disease and discussion of complications with the patient should be done. Maternal disease should be stable before pregnancy. The severity of organ involvement and antibodies present (topoisomerase 1, anti-centromere, anti-RNA polymerase 3, anti-Ro/SSA, anti-La/SSB, anticardiolipin, beta 2 glycoprotein, and lupus anticoagulant) should be documented. [20]
Vasculopathy
General measures to avoid sudden temperature changes must be taken. Nifedipine at doses <60 mg/day is compatible with pregnancy and breastfeeding. [21] There is limited evidence of use of 5-phosphodiesterase inhibitors such as sildenafil. [8],[21]
Most drugs used for this purpose are contraindicated (cyclophosphamide, methotrexate, mycophenolate mofetil). [22]
Joint manifestations
Paracetamol may be used, as well as low doses of prednisolone (<15 mg/day) and hydroxychloroquine. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be minimally used only in the second trimester and must be withdrawn at 32 weeks due to their association with premature closure of the ductus arteriosus. [21] Codeine and tramadol are compatible with pregnancy, but caution and short-term use only are recommended when breastfeeding. [21] Rituximab is not safe during pregnancy or breastfeeding and should be stopped 6 months before pregnancy. [22]
Gastrointestinal manifestations
Proton pump inhibitors and histamine receptor blockers can be used. [8],[23] Pregnancy should be discouraged in cases of serious disorders of intestinal absorption. [6]
Pulmonary fibrosis and pulmonary arterial hypertension
Pregnancy should be discouraged in severe disease (FVC <50%) and PAH. [12] It is recommended to perform an echocardiogram before pregnancy and during any clinical deterioration. In case of pregnancy, the patient should be treated in a tertiary level center and continue specific treatment for PAH as needed, particularly during the second and third trimester of pregnancy, during and after delivery. At this stage, phosphodiesterase 5 inhibitors including sildenafil, prostaglandin analogs such as iloprost or epoprostenol, nitric oxide, and supportive therapy with calcium channel antagonists and heparin anticoagulation can be used. [14],[24] The use of endothelin receptor antagonists is contraindicated during pregnancy. [21]
Cardiac manifestations
It is recommended to avoid pregnancy in cases of left severe ventricular dysfunction (ejection fraction <30%). [6]
Renal crisis
Enalapril is the drug of choice in the management of renal crisis and should be used indefinitely to control blood pressure. Although enalapril is contraindicated in pregnancy because of the risk of fetal toxicity such as anhydramnios, renal atresia, pulmonary hypoplasia, and fetal death, it should be used indefinitely in SSc renal crisis as the risk of maternal complications far exceeds the fetal risk. [7] The treatment of a renal crisis may require dialysis temporarily or for even up to 2 years after the renal crisis till the renal function recovers. [25] If there is a risk to maternal or fetal life, termination of pregnancy may be considered in the first trimester or induction of labor in the third trimester.
Pregnancy does not improve the symptoms of ankylosing spondylitis (AS). [3],[26],[27] In many patients, disease activity is not substantially altered during pregnancy. Two prospective studies have shown active disease during the first and early second trimester, with a flare around week 20 of pregnancy. [3],[27] Active AS produces increased pain and stiffness of the spine, intensified nocturnal pain, and occasionally acute arthritis in peripheral joints. In some patients, pain at the attachment sites of ligaments or tendons and a feeling of tightness in the chest create additional problems. Anterior uveitis can become active during this period. Need for NSAIDs and analgesics may be present in about 70% of the patients. Disease activity may decrease in the third trimester.
Twenty percent of AS patients improve from spinal and extra-spinal symptoms during pregnancy. [3],[26] Most often, these patients have a history of extra-axial symptoms such as peripheral arthritis, psoriasis, or inflammatory bowel disease associated with their AS. In patients with multiple pregnancies, no uniform pattern regarding remission or flare is seen. Complete remission of symptoms never occurs in any patient with pure spinal disease.
Maternal disease activity postpartum
About 50%-80% of the AS patients have a flare 4-12 weeks after delivery. [3],[26] Episodes of acute peripheral arthritis or anterior uveitis occur 1.5-3 times more often after delivery than during pregnancy. [26]
Course of pregnancy and delivery
The rate of miscarriage, stillbirth, prematurity, and IUGR is similar to healthy women. [26] Compared to healthy women, cesarean section is more frequently performed in patients with AS. [26] Inflammation or ankylosis of the sacroiliac joints is not a mechanical hindrance for the progression of labor.
Paracetamol, codeine, and tramadol are safe to use in periconception, throughout pregnancy and with caution in the case of codeine and tramadol when breastfeeding. [21] Nonselective NSAIDs can be used in the first trimester, used with caution in the second trimester, and stopped by the 32 nd week. Cox 2 inhibitors are not advised in periconception, pregnancy, and lactation. [21]
Disease-modifying anti-rheumatic drugs and biologics
Prednisolone and methyl prednisolone can be used in periconception, pregnancy, and lactation. Sulfasalazine with folic acid supplementation can safely be used throughout pregnancy and lactation. Methotrexate and leflunomide are not safe in pregnancy and lactation. Methotrexate should be stopped 3 months before conception, and cholestyramine washout is needed before conception in case of previous leflunomide use. Anti-tumor necrosis factor agents such as etanercept, infliximab, and adalimumab can all be used until 16 weeks of pregnancy (with etanercept and adalimumab until 24 weeks) and postpartum although there are very limited data on breastfeeding. There are no data on golimumab usage in pregnancy or lactation, but certolizumab can be used throughout pregnancy and lactation as with no Fc component in the monoclonal antibody it does not cross the placenta significantly. [22]
Polymyositis and dermatomyositis
Majority of female patients are diagnosed or develop idiopathic inflammatory myopathies (IIM) after the reproductive years. [5],[28] In a series of 28 patients with IIM, the mean age of patients with pure polymyositis/dermatomyositis (PM/DM) was 41 years while the mean age of patients of overlap syndrome with myositis was 32 years. [28]
Polymyositis and dermatomyositis during pregnancy and pregnancy outcome
A 2003 review of all reported cases in the literature of pregnancy and myositis indicates that up to 50% of the patients have established disease before pregnancy, 35% manifest with IIM during pregnancy, and in 15%, myositis starts postpartum. [28] On the contrary, a study by Vαncsa et al. on 173 female patients with IIM found that 104 patients had 186 pregnancies. [29] Only nine of these patients became pregnant after onset of disease resulting in 14 pregnancies. Similarly, the study by Pinal-Fernandez et al. from Spain of the pregnancy outcomes among 51 women with IIM who had a total of 102 pregnancies also show that only 14 pregnancies from eight women occurred after disease onset. [30] Both these studies seem to suggest that lesser number of pregnancies occur after onset of IIM again as discussed above which could be that onset of IIM is after the reproductive years.
Pregnancy outcome in mothers with IIM varies with disease severity. In patients with active disease during pregnancy, 45% may end in spontaneous abortion or neonatal death and 30% of infants show IUGR. [28],[29] Patients with inactive IIM during pregnancy deliver healthy babies with normal birth weight in more than 85% of cases. [28],[29]
Active PM/DM during pregnancy should be treated with high dose prednisone up to 1 mg/kg/day and maintained until the normalization of serum creatine kinase levels. If the response to prednisone is insufficient, cyclosporine A or azathioprine can be added. In IIM refractory to high-dose corticosteroid treatment, intravenous immunoglobulin can be safely used during pregnancy. [31]
The majority of women with SSc can have successful pregnancies with little risk of serious complications if the extent of disease is assessed, risk is stratified and discussed with the patient, and close monitoring is done in pregnancy with combined care of obstetrician and rheumatologist
Pregnancy in women with SSc should be considered high risk due to increased risk of hypertension, premature delivery, and IUGR
In early pregnancy, patient with SSc should be carefully assessed to establish the disease subtype (diffuse or limited), early or late disease, and the extent of organ involvement
SSc early disease (<4 years), diffuse subtype, or anti-topoisomerase 1 or anti-RNA polymerase 3 antibodies have higher obstetric risk and, if possible, should delay pregnancy until the disease is in late stage and therefore less active disease
The third trimester of pregnancy is the one with the highest maternal risk since the patient may develop complications secondary to hypertension, renal failure, pulmonary hypertension, interstitial lung disease, or heart failure
There is no other significant change in the activity of the SSc during pregnancy
Patients with SSc have no fertility problems resulting from their disease
Pregnancy does not improve axial symptoms of AS
Disease activity is not substantially altered in patients with AS during pregnancy
The rate of miscarriage, stillbirth, prematurity, and IUGR is similar to healthy women in AS
Most women with PM/DM with inactive disease at conception have normal pregnancies with a good outcome
Women with active PM/DM disease at conception or disease onset during pregnancy are at high risk of an adverse pregnancy outcome.
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1 Poor maternal and foetal outcomes in women with systemic sclerosis: an interview-based study at a tertiary centre
Rajat Kharbanda,R. Naveen,Durga Prasanna Misra,Latika Gupta,Vikas Agarwal
Rheumatology International. 2021;
Rao VK
polymyositis
Immunology of Pr...
Cytokines and th...
Ankylosing Spond...