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- Antiphospholipid Antibodies
- Antiphospholipid Syndrome
- Multidisciplinary team-care
- Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS), SLE-associated or primary APS, affect mostly women of childbearing age. Several ‘unmet needs’ in the management of reproductive and other women's health issues may impact on personal relationships and the decision to have children.1 Because of earlier recognition of disease and advances in medical treatment, family planning has gained greater importance.2–4 Concerns include the effect of pregnancy on maternal disease, the impact of disease activity on fetal health and the safety of medications during pregnancy and breast feeding. Assessment of fertility and feasibility of assisted reproduction techniques (ARTs), use of contraception, management of menopause and surveillance against malignancies need to be addressed. We gathered a multidisciplinary panel of experts to develop evidence-based recommendations on the management of family planning and women's health issues in SLE and/or APS.
We followed the European League Against Rheumatism (EULAR) standardised operating procedures5 and the Appraisal of Guidelines Research and Evaluation instrument. Through a Delphi-based approach, the committee selected 12 research questions further edited for systematic literature review (see online supplementary table S1). We searched PubMed using arrays of relevant terms; all English-language publications up to December 2014 were considered. A hand search was also performed in October 2015. Retrieved items were refined based on abstract, full-text content and number of included patients. A detailed presentation of the literature review is given in the online supplementary table S2. Evidence was categorised based on the design and validity of available studies and the strength of the statements was graded (see online supplementary table S3). After rounds of discussions, the committee arrived at 12 final statements (table 1). Each member rated her/his agreement with each statement.
Research questions selected for the systematic literature search and keywords used for the Pubmed search
Summary of the results of systematic literature review
Level of evidence (LoE) and grade of recommendation (GoR) rating scales
Results and discussion
Scope and overarching principles
These recommendations have been devised with the intention of helping physicians involved in the care of patients with SLE and/or APS and facilitating physician–patient communication. They recognise an implicit need for change in the mindset of health professionals, shifting from caution against pregnancy towards embracement of pregnancy. Accordingly, family planning should be discussed from the first physician–patient encounter and reinforced thereafter. Health professionals should support the patient and her family in their decisions regarding family planning by discussing individual pregnancy risks. Reports on the long-term follow-up of SLE and/or APS offspring are few,7–10 showing a reassuring picture on the health conditions of the children, with the exception of some cases of neurodevelopmental alterations11–13 that need further confirmation before they are linked to maternal disease.
Preconception counselling and risk stratification
Assessment of risk factors for adverse maternal and fetal outcomes in pregnant women with SLE and/or APS is crucial for preconception counselling and implementing appropriate preventive strategies and patient-tailored monitoring plan before and during pregnancy (table 2).
In SLE women (with or without APS), prematurity, pre-eclampsia and eclampsia/Hemolysis, Elevated Liver enzyme levels, Low Platelet count (HELLP) rates approximate 25–35%, 10–15% and 1.0–1.5%, respectively.19 ,24 ,25 ,44 ,51 ,52 In APS women (primary or SLE-related), the respective frequencies approximate 25–35%, 10–20% and 3.0–5.0%.28 ,29 ,53 ,54
During pregnancy, risk factors associated with adverse outcomes include active/flaring SLE (OR 12.7 for pre-eclampsia/eclampsia;55 19.0 for emergency caesarean section;56 3.0 for early fetal loss;20 5.5 for preterm delivery),21 ,19 active nephritis (OR 5.3 for any adverse maternal outcome),57 hypertension (OR 4.8–7.3 for pre-eclampsia;52 relative risk (RR) 1.8 for preterm birth)22 and use of glucocorticoids, especially at maintenance dose ≥10–20 mg/day of prednisone equivalent (OR 3.5 for preterm birth).58 ,59 Discontinuation of hydroxychloroquine (HCQ) is related to an increased risk for SLE exacerbations during pregnancy,24 ,33 ,56 and a single placebo-controlled study has suggested a beneficial effect of HCQ on maternal disease activity during pregnancy.60
Women with SLE and/or APS should be counselled about contraception, especially for the prevention of unwanted pregnancies during high disease activity periods and intake of teratogenic drugs. Effective contraceptive measures should be discussed with the patient by weighing the individual risk factors, including general (hypertension, obesity, tobacco use, family history of hormonal-dependent cancers)61 and disease-related risk factors, particularly disease activity and thrombotic risk (emphasis on antiphospholipid antibodies (aPLs)).
The intrauterine device (IUD) can be offered to all patients unless there is a gynaecological contraindication. Copper IUD can be used in any patient, while levonorgestrel-containing IUD should be considered only if the benefits of the released hormone (such as the reduction of excessive menstrual bleeding due to anticoagulation)62 outweigh the risk of thrombosis.61
The safety of the combined (oestrogen plus progestin) and progestin-only pill in SLE patients with inactive or stable active SLE and negative aPL has been demonstrated in randomised controlled trials (RCTs).63 ,64 In women with positive aPL (with or without definite APS), contraception with combined hormones (oral pill, vaginal ring, transdermal patch) should be discouraged. In young women with myocardial infarction or ischaemic stroke and positive lupus anticoagulant, the use of the combined pill increased the risk of arterial events compared with non-users.65 In fully anticoagulated patients carrying a low-risk aPL profile, oestrogens might be considered for persistent gynaecological disorders not otherwise managed. Compounds containing progestin only (pill, subcutaneous depot injections) are suitable for these women, although their use should be weighed against the risk of thrombosis. Progestin-only emergency contraception is not contraindicated in patients with SLE and/or APS.
Risk factors for reduced fertility
Few studies have assessed fertility in women with SLE and/or APS by means of hormonal levels (including the anti-Müllerian hormone) or antral follicle count (examined by ultrasound). There is no concrete evidence that the disease per se decreases fertility.66–69
However, active disease, especially lupus nephritis, and the use of immunosuppressive drugs may negatively impact on fertility. Alkylating agents such as cyclophosphamide (CYC) may cause menstrual irregularities and premature ovarian failure (POF), which is age- and dosage dependent.70 ,71
Similar to the general population, women with SLE and/or APS should be counselled on fertility issues, especially on the negative impact of increasing age (general tendency to postpone childbearing) and certain lifestyle exposures (tobacco use, alcohol consumption). In non-life-threatening disease, treatment with alkylating agents should be balanced against the risk of ovarian dysfunction; rather, less gonadotoxic regimens should be considered.72 In the presence of multiple risk factors for impaired fertility, ovarian reserve may be assessed in patients with SLE at a younger age than recommended for the general population.73
Limited data are available on fertility preservation methods in menstruating women with SLE who require treatment with alkylating agents. Cryopreservation of ovarian tissue or oocytes/embryos are poorly investigated options74 ,75 and require specialised centres, which may not be easily accessible.
The most extensively studied method for POF prevention in patients with SLE involves gonadotropin-releasing hormone analogues (GnRH-a), with a good safety and efficacy profile (RR 0.12).76 GnRH-a have been efficacious in patients with cancer.77 ,78 GnRH-a are likely to protect against POF, but there are no data on subsequent pregnancies in patients with SLE. They can cause menopause-like symptoms, which are fully reversible upon discontinuation. A study in childhood-onset patients with SLE aged <21 years suggested that GnRH-a should be administered 22 days before CYC is started or continued.79 It is nevertheless recommended to start the GnRH-a prior to or concomitantly to initiation of the alkylating agent.
Assisted reproduction techniques
Evidence on the efficacy and safety of ARTs (ovulation induction therapy and in vitro fertilisation) in women with SLE and/or APS comes from observational studies.80–83 Efficacy in terms of pregnancy rate is comparable with that in the general population (up to 30%). ARTs are generally safe if the patient has quiescent disease and is on appropriate antithrombotic treatment if aPL positive. Although it is challenging to define a single protocol, some general measures for prophylaxis in aPL-positive women undergoing ovarian stimulation can be suggested. The type (low-dose aspirin (LDA); low molecular weight heparin (LMWH)) and dosage (prophylactic vs full anticoagulant) of antithrombotic treatment should be recommended as during pregnancy according to the individual risk profile. LDA should be stopped three days before egg retrieval and resumed the following day. Patients taking LMWH should stop it at least 12 hours prior to the procedure and resume it the very same day as long as there is no bleeding. Patients with positive aPL who are not taking LDA during the ovarian stimulation period should start LDA on the day of the embryo transfer, usually in combination with LMWH (which will be continued during pregnancy).
Ovarian hyperstimulation syndrome can be avoided by milder hormonal stimulation or GnRH antagonist protocol.84 The use of the ‘natural cycle’ method is another option, although associated with a lower rate of induced pregnancy. The ART induction protocol should be tailored to the individual patient, balancing the safety and effectiveness of the procedure.
Predictive biomarkers for maternal disease activity in SLE pregnancy
Active SLE during pregnancy, assessed by validated disease activity indices22 ,56 and/or physician global assessment,20 is associated with increased risk for maternal and/or fetal complications (see also paragraph on Preconception counselling and risk stratification). Pregnancy-specific SLE activity indices have been developed and validated for their sensitivity in detecting changes in disease activity and diagnosing flares (see online supplementary table S4).85 ,86 Physicians should be aware of pregnancy physiological changes that can resemble SLE symptoms and signs.87 Renal activity correlates with adverse pregnancy outcomes and should be monitored by means of urine protein excretion, urine sediment analysis (glomerular haematuria, urinary casts) and serum creatinine level/glomerular filtration rate.33 ,49 ,52 Serological markers are useful in monitoring SLE activity and in the differentiation between disease exacerbation (declining serum C3/C4 levels (even within the normal range) and/or increasing anti-double stranded DNA titres) and pre-eclampsia.88 ,89 Smaller increases in serum C3 levels from pregnancy onset to the second or third trimester19 as well as serological activity (as defined above) that develops during pregnancy, especially in the context of clinical SLE activity, have been associated with increased risk for pregnancy loss,19 ,90 intrauterine growth restriction (IUGR)91 and preterm birth.19 ,48 ,89 ,90 ,92
Assessment of disease activity during pregnancy in women with SLE
Pregnant women with SLE and/or APS should follow the local protocols applied to pregnancies at high risk for hypertensive disorders and/or placental insufficiency, adjusting the frequency and modality of fetal surveillance according to the maternal and/or fetal status (box 1). Fetal surveillance based on biometric and Doppler findings during the third trimester, and particularly the distinction between early and late IUGR, helps to better tailor the time of delivery and reduce perinatal morbidity and mortality.93–97 Umbilical and uterine arteries Doppler sonography at 20–24 weeks has good negative predictive value but modest positive predictive value (especially in the absence of biometric signs of fetal growth restriction later in pregnancy) for placental-associated pregnancy disorders such as pre-eclampsia and IUGR. The mode (vaginal vs caesarean section) and timing of delivery are influenced by maternal (hypertensive disorders, anticoagulation status) as well as fetal conditions during pregnancy.
Ultrasonographic fetal surveillance recommended for pregnant women with systemic lupus erythematosus and/or antiphospholipid syndrome43,45–48
Routine ultrasonographic screening
First trimester (11–14 weeks of gestation).
Second trimester (with Doppler, preferably at 20–24 weeks of gestation).
Supplementary fetal surveillance in the third trimester at monthly intervals
Doppler sonography of the umbilical artery, uterine arteries, ductus venosus and middle cerebral artery (particularly in fetuses that have been identified to suffer from early intrauterine growth restriction (IUGR), ie, prior to 34 weeks of gestation).
In cases of late IUGR (diagnosed after 34 weeks), reduced abdominal circumference growth velocity and/or a reduced cerebroplacental ratio at Doppler investigation was shown to identify fetuses at higher risk of poor perinatal outcome (Doppler of the umbilical artery alone is insufficient).
Fetal echocardiography is indicated if there is suspected fetal dysrhythmia or myocarditis, especially in the context of positive maternal anti-Ro/SSA or anti-La/SSB antibodies. Other tests (electrocardiogram plus Holter monitor, magnetocardiography, gated-pulsed Doppler technique, velocity-based fetal kinetocardiogram) might detect subtle signs of the development of congenital heart block (CHB), but are not currently recommended as standard practice.98 CHB associated with anti-Ro/SSA and/or anti-La/SSB has 16% recurrence rate in women with a previously affected child; therefore, it is recommended to perform serial fetal echocardiograms weekly from 16 weeks of gestation onwards.98 Considering the low risk (0.7–2%) for CHB in women with no previous CHB, it is unclear whether intensive monitoring (weekly/biweekly between 16 and 26 weeks of gestation and less frequently afterwards)98 in the general population of anti-Ro/La-positive women is cost-effective. Moreover, there is no proven efficacy of protocols for the prevention or treatment of complete CHB.99 ,100 The efficacy of maternal fluorinated steroids has not been established in large cohorts101–104 despite initial reports of favourable effects in cases of incomplete CHB, cardiomyopathy, endocardial fibroelastosis and hydrops fetalis.99 Given the potential of fluorinated steroids for major maternal and fetal side effects, the benefit for fetuses with CHB should be stratified according to the presence of risk factors for adverse outcome.99 Despite its unproven benefit, the current practice of intensive surveillance for CHB onset in women with positive anti-Ro/SSA and/or anti-La/SSB antibodies and no previous child affected by CHB carries no risk and is well accepted by the mothers.105
Drugs for prevention and management of SLE flares during pregnancy
A single randomised, placebo-controlled study60 as well as non-randomised evidence24 ,33 ,56 supports the beneficial role of HCQ in controlling disease activity and preventing flare-ups during pregnancy. Uncontrolled studies suggest an acceptable benefit/risk ratio of oral glucocorticoids,22 ,106 azathioprine59 ,107 and calcineurin inhibitors (ciclosporin A, tacrolimus)108 ,109 in controlling SLE activity during pregnancy. In moderate-to-severe flares, additional modalities can be considered, such as high-dose glucocorticoids (including pulse intravenous therapy),110 ,111 intravenous immunoglobulin20 ,22 and plasmapheresis (may be also used in refractory nephrotic syndrome).112 ,113 CYC should not be administered during the first trimester of pregnancy due to risk for fetal loss (OR 25.5)20 ,114 and should be reserved only for the management of severe, life-threatening or refractory SLE manifestations during the second or third trimester. Available data are not sufficient to evaluate the risk of using belimumab in pregnancy115 and the drug should not be used unless the benefit outweighs the risk to the fetus. Mycophenolic acid, methotrexate and leflunomide should be avoided due to known or possible teratogenicity.116 To this end, collaborative groups have developed recommendations for the use of antirheumatic drugs before and during pregnancy and lactation.111 ,117 ,118
Adjunct treatment during pregnancy
Use of HCQ is recommended in women with SLE preconceptionally and throughout pregnancy.33 ,56 ,60 A beneficial role has also been suggested for APS pregnancies,119–121 but at present there is insufficient data to recommend its routine use in these patients. HCQ may reduce the odds of CHB occurrence in fetuses exposed to maternal anti-Ro/SSA antibodies, especially in mothers who already had a child with CHB.40 ,122
The protective role of LDA against preterm and severe pre-eclampsia has been established in non-autoimmune patients.123 ,124 Accordingly, women with SLE at higher risk of pre-eclampsia including those with lupus nephritis or positive aPL will benefit from LDA, preferably given preconceptionally or no later than gestational week 16.123 ,124
In women with definite obstetric APS, combination treatment with LDA and heparin is recommended to decrease the risk of adverse pregnancy outcomes.16 ,125–127 Statistically significant results have been demonstrated only for unfractionated heparin in RCTs. However, LMWH is preferable for practical reasons and has shown comparable efficacy in prospective studies.128 ,129 Moreover, patients with positive aPL but with no definite classification of APS will benefit from combination therapy if they are considered at moderate to high risk of maternal and fetal complications (see online supplementary table S5).
Assessment of disease activity during pregnancy in women with SLE
In addition, other regimens such as prednisolone 10 mg/day in the first trimester, intravenous immunoglobulin or plasmapheresis can be considered for selected patients with APS (refractory obstetric APS, women with previous thrombosis, particularly previous or new cerebrovascular events, women with triple aPL positivity).119 ,130–133
As recommended in the general population, supplementation with calcium, vitamin D and folic acid should be offered to patients with SLE and/or APS, with particular consideration to those with low circulating levels of 25-OH vitamin D in the first trimester of gestation and receiving glucocorticoids and/or heparin for their detrimental effects on bone mass.
Menopause and hormone replacement therapy
The efficacy and safety of hormone replacement therapy (HRT) (oestrogen plus progestin) in selected patients with SLE has been illustrated in RCTs.134–136 Benefit was demonstrated mainly in vasomotor and other hypoestrogenism symptoms. No significantly increased risk of severe lupus exacerbations during 12–24 months of HRT was found, although there was a modest increase in mild-to-moderate flares.132 There was no increased risk of thrombosis and cardiovascular events, although one of the RCTs included only patients with negative aPL and no previous cardiovascular events132 and another did not detail the aPL profile.63 Two cohort studies with long-term follow-up did not report significantly increased risk of cardiovascular events during HRT,137 ,138 although limitations in power and design preclude firm conclusions. Consequently, HRT should be reserved for the management of severe and disabling vasomotor menopausal symptoms, preferably in SLE women with stable/inactive disease and negative aPL. In patients with positive aPL, the use of HRT should be carefully weighed against thrombotic and cardiovascular risks. If menopause symptoms necessitate HRT, it seems reasonable to start it as early as possible to gain an added benefit for bone protection.139 Optimal duration of HRT in patients with SLE and/or APS is not known, but it seems reasonable to recommend it for the shortest possible duration.140 ,141
Screening for malignancies
Women with SLE are not at increased risk of breast, ovarian and endometrial cancer compared with the general population,142 ,143 and, therefore, should follow the current population screening protocols for these malignancies. Conversely, women with SLE are at higher risk of cervical dysplasia (but not cervical cancer),144–147 vagina and vulva cancers,142 ,147 likely associated with human papillomavirus (HPV) infection. Women with SLE exposed to immunosuppressive drugs, particularly CYC in a cumulative dose-dependent fashion, are at higher risk of cervical dysplasia.148–151 The suggested timing for Papanicolaou (PAP) smear examination would be once a year in heavily immunosuppressed patients or according to the local screening programme in low-risk patients. Subgroups of women with SLE (Caucasian, younger age, lower education, high SLE damage) may be at risk for poorer adherence to screening programmes.152 ,153
HPV vaccination is currently offered to female and male adolescents for preventing precancerous growths and cancer in the cervix and in the genital area. There are reports of venous thromboembolic events (VTEs) associated with the quadrivalent HPV vaccine. However, of the 31 cases (0.2/100 000 doses vaccine) with documented VTE, 90% had a known risk factor for VTE (APS in two cases).154
Prospective studies have demonstrated efficacy and safety of HPV vaccination in patients with SLE,155 ,156 although seroconversion rates may be lower in patients receiving steroids and immunosuppressive agents. A few cases of severe SLE flares or abrupt SLE onset after HPV vaccination have been reported.157–159 In accordance with the EULAR recommendations,160 we recommend that HPV vaccination be offered to young women with stable/inactive SLE and/or APS, according to local protocols, with particular caution in those with high-risk aPL profile.
The points to consider and the research agenda suggested by the Task Force Members are reported in box 2.
Points to consider and research agenda
Reproductive issues are of paramount importance for women with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) and should be addressed on a regular basis by healthcare providers.
Preconception counselling and risk stratification are essential for prevention of unwanted complications during pregnancy.
The use of hormonal contraception or replacement therapy is feasible but must be weighed against the individual risk of thrombosis.
The preservation of fertility should be mentioned while counselling about lifestyles and considered in the treatment choice. Validated protocols for assisted reproduction techniques in patients with SLE and/or APS are needed.
Predictive biomarkers for maternal disease activity during SLE pregnancy should be expanded with particular focus on the prediction of pre-eclampsia.
Pregnancy monitoring in SLE and/or APS women should aim at the identification of placental insufficiency with fetal growth restriction in order to decide the best timing for delivery and reduce the risk of perinatal morbidity and mortality.
The cost-effectiveness of intensive surveillance with fetal echocardiography in patients with positive anti-Ro/SSA and anti-La/SSB antibodies and no previous child with congenital heart block remains to be established.
Hydroxychloroquine is beneficial during pregnancy to reduce the risk of SLE flares and of poor obstetrical outcomes. More data are needed to support its benefit in APS pregnancies.
The benefits of cancer surveillance and prevention of gynaecological malignancies need to be communicated to patients.
The committee wishes to acknowledge the support of the EULAR Standing Committee on Clinical Affairs. The committee also expresses its sincere appreciation and gratitude to the EULAR Secretariat and especially to Patrizia Jud, executive assistant, for outstanding organisation.
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