EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome

Objectives Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). Methods Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus.

# Introduction
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. [bib_ref] New insights into sexual functioning and fertility in rheumatic diseases, stensen [/bib_ref] Because of earlier recognition of disease and advances in medical treatment, family planning has gained greater importance. [bib_ref] Women's health and fertility, family planning and pregnancy in immune-mediated rheumatic diseases:..., Ntali [/bib_ref] [bib_ref] Proceedings from the American College of Rheumatology Reproductive Health Summit: the management..., Kavanaugh [/bib_ref] [bib_ref] State of the art: reproduction and pregnancy in rheumatic diseases, stensen [/bib_ref] 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 evidencebased recommendations on the management of family planning and women's health issues in SLE and/or APS.

# Methods
We followed the European League Against Rheumatism (EULAR) standardised operating procedures 5 and the Appraisal of Guidelines Research and Evaluation instrument. Through a Delphibased 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 10 (0) 9. Adjunct treatment during pregnancy 9.1 HCQ is recommended preconceptionally and throughout pregnancy for patients with SLE (2/B). 9.2 Women with SLE at risk of pre-eclampsia (especially those with lupus nephritis or positive aPL) should receive LDA (2/C). In women with SLE-associated APS or primary APS, combination treatment with LDA and heparin is recommended to decrease the risk of adverse pregnancy outcomes (1/A). 9.6 (0.6) 10 (1) 11. Screening for malignancies Women with SLE and/or APS should undergo screening for malignancies similar to the general population (-/D). Women with SLE, especially those exposed to immunosuppressive drugs, are at higher risk of cervical premalignant lesions and should be monitored with vigilance (2/B). For each statement or item, the LoE (range 1-3) and the GoR (range A-D) is given in parentheses (refer to online supplementary table S1). In the right-hand columns, the LoA among experts is reported as mean (SD) and median (IQR) values. A score of 10 represents the highest level of agreement. *aPL and APS are defined according to the updated international consensus criteria. [bib_ref] International consensus statement on an update of the classification criteria for definite..., Miyakis [/bib_ref] For aPL assays, please see the footnotes of table 2. The substatement on fetal echo in women with SLE/APS and positive anti-Ro/La is rated with LoE=2 (ie, sufficient evidence for the association between anti-Ro/La and congenital heart block) but GoR=C due to lack of strong evidence for the clinical implications of this association, namely for the efficacy of interventions. anti-dsDNA, anti-double-stranded DNA antibodies; aPL, antiphospholipid antibodies; GnRH, gonadotropin-releasing hormone; GoR, grade of recommendation; HCQ, hydroxychloroquine; HPV, human papillomavirus; HRT, hormone replacement therapy; IUD, intrauterine devices; LDA, low-dose aspirin; LoA, level of agreement; LoE, level of evidence.
discussions, the committee arrived at 12 final statements [fig_ref] Table 1: Recommendations for women's health and the management of family planning, assisted reproduction,... [/fig_ref]. Each member rated her/his agreement with each statement.

## 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 alterations 11-13 that need further confirmation before they are linked to maternal disease.

## Recommendations

## 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 . In SLE women (with or without APS), prematurity, preeclampsia and eclampsia/Hemolysis, Elevated Liver enzyme levels, Low Platelet count (HELLP) rates approximate 25-35%, 10-15% and 1.0-1.5%, respectively. [bib_ref] Predictors of pregnancy outcomes in patients with lupus: a cohort study, Buyon [/bib_ref] In APS women (primary or SLE-related), the respective frequencies approximate 25-35%, 10-20% and 3.0-5.0%. [bib_ref] Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS..., Bouvier [/bib_ref] During pregnancy, risk factors associated with adverse outcomes include active/flaring SLE (OR 12.7 for pre-eclampsia/ eclampsia; [bib_ref] Efficacy and safety of mycophenolate mofetil versus cyclophosphamide for induction therapy of..., Liu [/bib_ref] [bib_ref] Predictors of pregnancy outcomes in patients with lupus: a cohort study, Buyon [/bib_ref].0 for emergency caesarean section; [bib_ref] Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus..., Koh [/bib_ref] 3.0 for early fetal loss; 20 5.5 for preterm delivery), 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) [bib_ref] Factors that predict prematurity and preeclampsia in pregnancies that are complicated by..., Chakravarty [/bib_ref] and use of glucocorticoids, especially at maintenance dose 10-20 mg/day of prednisone equivalent (OR 3.5 for preterm birth). Discontinuation of hydroxychloroquine (HCQ) is related to an increased risk for SLE exacerbations during pregnancy, and a single placebo-controlled study has suggested a beneficial effect of HCQ on maternal disease activity during pregnancy. [bib_ref] Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study, Levy [/bib_ref] 

## Contraceptive measures
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 Checklist of parameters to be considered for preconception counselling and risk stratification in women with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS)

# Disease-related risk factors
Prognostic implications SLE activity/flares* (in the last 6-12 months or at conception)
Increased risk for (i) maternal disease activity (RR 2.1 for subsequent flare during pregnancy and puerperium); [bib_ref] Pregnancy-related systemic lupus erythematosus: clinical features, outcome and risk factors of disease..., Yang [/bib_ref] (ii) hypertensive complications (OR 1.8 for PE); [bib_ref] Predictors of maternal and fetal outcomes in pregnancies of patients with systemic..., Kwok [/bib_ref] (iii) fetal morbidity and mortality (OR 5.7 for pregnancy loss, [bib_ref] Early administration of low-dose aspirin for the prevention of severe and mild..., Roberge [/bib_ref] 3.5 for IUGR [bib_ref] Renal biopsy in the management of lupus nephritis during pregnancy, Chen [/bib_ref] 6.5 for preterm delivery) [bib_ref] Pregnancy-related systemic lupus erythematosus: clinical features, outcome and risk factors of disease..., Yang [/bib_ref] Lupus nephritis (history or active at conception )
Strong predictor of poor maternal (RR 9.0 for renal flare during/after pregnancy) [bib_ref] Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal..., Imbasciati [/bib_ref] and fetal outcome(s) (OR 7.3 for fetal loss and 18.9 for preterm delivery) Serological (serum C3/C4, anti-dsDNA titres) activity
Increased risk for maternal SLE flares during pregnancy (OR 5.3) [bib_ref] Pregnancy-related systemic lupus erythematosus: clinical features, outcome and risk factors of disease..., Yang [/bib_ref] and pregnancy loss Previous adverse pregnancy outcome(s) APS: increased risk for pregnancy complications [bib_ref] Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS..., Bouvier [/bib_ref] [bib_ref] Neonatal outcome in pregnant patients with antiphospholipid syndrome, Jeremic [/bib_ref] [bib_ref] Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404..., Giron-Gonzalez [/bib_ref] History of vascular thrombosis APS: increased risk (ORs ranging 3.6-12.7) for pregnancy morbidity 31 SLE diagnosis APS: increased risk (OR 6.9) for pregnancy morbidity aPL profile  SLE: strong predictor of adverse maternal and fetal outcomes, especially for patients with persistent moderate-to-high aPL titres, LA and multiple aPL positivity (high-risk aPL profile) APS: high-risk aPL profile correlates with increased risk of maternal vascular thrombotic events during pregnancy (OR 12.1), [bib_ref] Primary antiphospholipid syndrome in pregnancy: an analysis of outcome in a cohort..., Stone [/bib_ref] (pre-)eclampsia (OR 2.3), APS-related pregnancy morbidity (OR 9.2), 31 IUGR (OR 4.7), [bib_ref] The association between antiphospholipid antibodies and placenta mediated complications: a systematic review..., Abou-Nassar [/bib_ref] preterm birth Anti-Ro/SSA, anti-La/SSB antibodies Linked to development of neonatal lupus, including a low risk (0.7-2%) for CHB (especially if moderate-to-high anti-Ro titres); [bib_ref] Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA..., Brucato [/bib_ref] [bib_ref] Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants..., Cimaz [/bib_ref] [bib_ref] Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165..., Costedoat-Chalumeau [/bib_ref] weak association with other pregnancy complications [bib_ref] Pregnancy outcomes among African-American patients with systemic lupus erythematosus compared with controls, Barnado [/bib_ref] End-stage organ damage and associated comorbidities General risk factors [bib_ref] Recurrent risk of adverse pregnancy outcome, Moore [/bib_ref] Maternal age
Arterial hypertension Increased risk for pregnancy loss (OR 2.4, 33 RR 2.9), 48 preterm birth and IUGR (OR 6.8) [bib_ref] Predictors of maternal and fetal outcomes in pregnancies of patients with systemic..., Kwok [/bib_ref] Diabetes mellitus [bib_ref] Maternal and fetal outcome of lupus pregnancy: a prospective study of 29..., Molad [/bib_ref] Overweight/obesity Thyroid disease [bib_ref] Thyroid disease in pregnant women with systemic lupus erythematosus: increased preterm delivery, Stagnaro-Green [/bib_ref] Nicotine and alcohol use [bib_ref] Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS..., Bouvier [/bib_ref] Immunisations  *Diagnosed by validated SLE activity indices and/or physician judgement. Evaluated by renal function tests (serum creatinine, blood urea nitrogen) and urinalysis (proteinuria urine sediment). Includes LA, aCL IgG/IgM, a2GPI IgG/IgM. The level of positivity of aCL and a2GPI antibodies (low vs medium-high) should be defined according to the single assay's characteristics. If negative serology, evaluate whether immunisations can be performed prior to pregnancy (eg, rubella). aCL, anticardiolipin antibodies; a2GPI, anti-2-GPI antibodies; anti-dsDNA, anti-double-stranded DNA antibodies; aPL, antiphospholipid antibodies; CHB, congenital heart block; IUGR, intrauterine growth restriction; LA, lupus anticoagulant; PE, pre-eclampsia; RR, relative risk. discussed with the patient by weighing the individual risk factors, including general (hypertension, obesity, tobacco use, family history of hormonal-dependent cancers)and diseaserelated 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) [bib_ref] Treatment of menorrhagia associated with oral anticoagulation: efficacy and safety of the..., Pisoni [/bib_ref] outweigh the risk of thrombosis.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). 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. [bib_ref] Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young..., Urbanus [/bib_ref] 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-Mullerian hormone) or antral follicle count (examined by ultrasound). There is no concrete evidence that the disease per se decreases fertility. [bib_ref] Effects of infertility, pregnancy loss, and patient concerns on family size of..., Clowse [/bib_ref] [bib_ref] Reproductive health in women with systemic lupus erythematosus compared to population controls, Ekblom-Kullberg [/bib_ref] [bib_ref] Study of anti-Mullerian hormone and its relation to the subsequent probability of..., Morel [/bib_ref] [bib_ref] Anti-Mullerian hormone in reproductive age women with systemic lupus erythematosus, Velarde-Ochoa Mdel [/bib_ref] 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. 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. [bib_ref] The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and..., Houssiau [/bib_ref] 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.

## Fertility preservation
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 options 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). [bib_ref] Pharmacological interventions for fertility preservation during chemotherapy: a systematic review and meta-analysis, Ben-Aharon [/bib_ref] GnRH-a have been efficacious in patients with cancer. 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. [bib_ref] Randomized, double-blind, dose-escalation trial of triptorelin for ovary protection in childhood-onset systemic..., Brunner [/bib_ref] 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. [bib_ref] Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid..., Guballa [/bib_ref] [bib_ref] Importance of planning ovulation induction therapy in systemic lupus erythematosus and antiphospholipid..., Huong [/bib_ref] [bib_ref] Subfertility treatment in women with systemic lupus erythematosus, Ragab [/bib_ref] [bib_ref] In vitro fertilization and systemic lupus erythematosus or antiphospholipid syndrome: an update, Orquevaux [/bib_ref] 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. [bib_ref] Ovarian stimulation for ovulation induction and in vitro fertilization in patients with..., Bellver [/bib_ref] 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 indices 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). Physicians should be aware of pregnancy physiological changes that can resemble SLE symptoms and signs. [bib_ref] Pregnancy and autoimmune diseases, Gordon [/bib_ref] 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. [bib_ref] Hydroxychloroquine in lupus pregnancy, Clowse [/bib_ref] 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 preeclampsia. Smaller increases in serum C3 levels from pregnancy onset to the second or third trimester [bib_ref] Predictors of pregnancy outcomes in patients with lupus: a cohort study, Buyon [/bib_ref] 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, intrauterine growth restriction (IUGR) [bib_ref] Hypocomplementemia correlates with intrauterine growth retardation in systemic lupus erythematosus, Kobayashi [/bib_ref] and preterm birth. [bib_ref] Predictors of pregnancy outcomes in patients with lupus: a cohort study, Buyon [/bib_ref] Pregnancy monitoring 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. [bib_ref] Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of..., Lees [/bib_ref] [bib_ref] 2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm..., Lees [/bib_ref] [bib_ref] Fetal and umbilical Doppler ultrasound in high-risk pregnancies, Alfirevic [/bib_ref] [bib_ref] An integrated model with classification criteria to predict small-for-gestational-age fetuses at risk..., Figueras [/bib_ref] [bib_ref] Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous..., Sovio [/bib_ref] 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 preeclampsia 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.
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. [bib_ref] The clinical spectrum of autoimmune congenital heart block, Brito-Zeron [/bib_ref] 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. [bib_ref] The clinical spectrum of autoimmune congenital heart block, Brito-Zeron [/bib_ref] 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) [bib_ref] The clinical spectrum of autoimmune congenital heart block, Brito-Zeron [/bib_ref] 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. [bib_ref] Prevention and treatment in utero of autoimmune-associated congenital heart block, Saxena [/bib_ref] [bib_ref] Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the..., Friedman [/bib_ref] The efficacy of maternal fluorinated steroids has not been established in large cohorts [bib_ref] Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic..., Izmirly [/bib_ref] [bib_ref] Isolated atrioventricular block in the fetus: a retrospective, multinational, multicenter study of..., Eliasson [/bib_ref] [bib_ref] Description of 214 cases of autoimmune congenital heart block: Results of the..., Levesque [/bib_ref] [bib_ref] Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac..., Izmirly [/bib_ref] despite initial reports of favourable effects in cases of incomplete CHB, cardiomyopathy, endocardial fibroelastosis and hydrops fetalis. [bib_ref] Prevention and treatment in utero of autoimmune-associated congenital heart block, Saxena [/bib_ref] 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. [bib_ref] Prevention and treatment in utero of autoimmune-associated congenital heart block, Saxena [/bib_ref] 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. [bib_ref] Ro/SSA autoantibody-positive pregnancy: reactions to serial fetal Doppler echocardiographic surveillance, Tingstrom [/bib_ref] Drugs for prevention and management of SLE flares during pregnancy A single randomised, placebo-controlled study [bib_ref] Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study, Levy [/bib_ref] as well as nonrandomised evidence [bib_ref] Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia, Arfaj [/bib_ref] 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, azathioprine and calcineurin inhibitors (ciclosporin A, tacrolimus) 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), intravenous immunoglobulin and plasmapheresis (may be also used in refractory nephrotic syndrome). CYC should not be administered during the first trimester of pregnancy due to risk for fetal loss (OR 25.5) 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 pregnancy 115 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. [bib_ref] How safe are anti-rheumatic drugs during pregnancy?, stensen [/bib_ref] To this end, collaborative groups have developed recommendations for the use of antirheumatic drugs before and during pregnancy and lactation. Adjunct treatment during pregnancy Use of HCQ is recommended in women with SLE preconceptionally and throughout pregnancy. [bib_ref] Hydroxychloroquine in lupus pregnancy, Clowse [/bib_ref] A beneficial role has also been suggested for APS pregnancies, [bib_ref] The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid..., Sciascia [/bib_ref] [bib_ref] The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid..., Sciascia [/bib_ref] [bib_ref] The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from..., Mekinian [/bib_ref] 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. The protective role of LDA against preterm and severe preeclampsia has been established in non-autoimmune patients. 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. In women with definite obstetric APS, combination treatment with LDA and heparin is recommended to decrease the risk of adverse pregnancy outcomes. 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. 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 .
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). Box 1 Ultrasonographic fetal surveillance recommended for pregnant women with systemic lupus erythematosus and/or antiphospholipid syndrome  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).
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. [bib_ref] The effect of combined estrogen and progesterone hormone replacement therapy on disease..., Buyon [/bib_ref] [bib_ref] Menopause hormonal therapy in women with systemic lupus erythematosus, Sanchez-Guerrero [/bib_ref] [bib_ref] Efficacy of estrogen plus progestin on menopausal symptoms in women with systemic..., Cravioto [/bib_ref] 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. [bib_ref] Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an..., Fischer-Betz [/bib_ref] 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 events 132 and another did not detail the aPL profile. [bib_ref] Combined oral contraceptives in women with systemic lupus erythematosus, Petri [/bib_ref] Two cohort studies with long-term follow-up did not report significantly increased risk of cardiovascular events during HRT, 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. [bib_ref] The pathophysiology and treatment of osteoporosis, Drake [/bib_ref] 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. Screening for malignancies Women with SLE are not at increased risk of breast, ovarian and endometrial cancer compared with the general population, 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), [bib_ref] Meta-analysis of systemic lupus erythematosus and the risk of cervical neoplasia, Liu [/bib_ref] [bib_ref] Systemic lupus erythematosus, human papillomavirus infection, cervical pre-malignant and malignant lesions: a..., Santana [/bib_ref] [bib_ref] Increased risk of high grade cervical squamous intraepithelial lesions in systemic lupus..., Zard [/bib_ref] [bib_ref] High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: a long-term..., Dreyer [/bib_ref] vagina and vulva cancers, 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. [bib_ref] Increased cervical dysplasia in intravenous cyclophosphamide-treated patients with SLE: a preliminary study, Bateman [/bib_ref] [bib_ref] Factors associated with abnormal Pap results in systemic lupus erythematosus, Bernatsky [/bib_ref] [bib_ref] Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus..., Ognenovski [/bib_ref] [bib_ref] Is higher prevalence of cervical intraepithelial neoplasia in women with lupus due..., Klumb [/bib_ref] 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. HPV vaccination 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). [bib_ref] Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine, Slade [/bib_ref] Prospective studies have demonstrated efficacy and safety of HPV vaccination in patients with SLE, 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. [bib_ref] Systemic lupus erythematosus following HPV immunization or infection?, Soldevilla [/bib_ref] [bib_ref] Human papillomavirus vaccine and systemic lupus erythematosus, Gatto [/bib_ref] [bib_ref] The safety of human papilloma virus-blockers and the risk of triggering autoimmune..., Baker [/bib_ref] In accordance with the EULAR recommendations, [bib_ref] EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases, Van Assen [/bib_ref] 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.
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.
Unit of Obstetrics and Gynaecology, Spedali Civili, Brescia, Italy
[fig] 9. 3: Supplementation with calcium, vitamin D and folic acid should be offered as in the general population (-/D). Measuring blood vitamin D levels should be considered after pregnancy is confirmed (-/D). Menopause and HRT HRT can be used for the management of severe vasomotor menopausal manifestations in SLE women with stable/inactive disease and negative aPL (1/A). The use of HRT in patients with positive aPL should be carefully weighed against the risk of thrombosis and cardiovascular disease (-/D). [/fig]
[table] Table 1: Recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) In women with SLE, major risk factors for adverse maternal and fetal outcomes include active/flaring SLE (1/A), especially active nephritis (1/A), history of lupus nephritis (2/B) and presence of aPL/APS* (1/A). 1.1.1 Blood pressure monitoring (2/B), use of safe medications to control disease activity (emphasis on HCQ (2/B)) and limiting glucocorticoids exposure (2/B) are essential measures. 1.2 In women with APS (primary or SLE-APS), risk factors include high-risk aPL profile (lupus anticoagulant, multiple aPL, moderate to high titre aPL) (1/A), coexisting SLE (2/B), history of vascular/thrombotic APS (2/B) and of previous adverse pregnancy complications (2/B). 1.2.1 Blood pressure monitoring (3/C) and use of antiplatelet and/or anticoagulant therapy (rated at statement 9) are of fundamental importance. In patients with stable/inactive SLE and negative aPL, combined hormonal contraceptives can be considered (1/A). Assisted reproduction techniques, such as ovulation induction treatments and in vitro fertilisation protocols, can be safely used in patients with SLE with stable/inactive disease (3/C).5.2 Patients with positive aPL/APS should receive anticoagulation (at the dosage as would be recommended during pregnancy) and/or low-dose aspirin (3/D). Predictive biomarkers for maternal disease activity in SLE pregnancyIn pregnant women with SLE, assessment of disease activity (1/A)-including renal function parameters (2/B) and serological markers (serum C3/C4, anti-dsDNA titres) (2/B)-is recommended to monitor for obstetrical adverse outcomes and disease flares. Women with SLE and/or APS should undergo supplementary fetal surveillance with Doppler ultrasonography and biometric parameters, particularly in the third trimester to screen for placental insufficiency and small for gestational age fetuses (3/D). 7.2 Fetal echocardiography is recommended in cases of suspected fetal dysrhythmia or myocarditis, especially in patients with positive anti-Ro/ Moderate-to-severe flares can be managed with additional strategies, including glucocorticoids intravenous pulse therapy, intravenous immunoglobulin and plasmapheresis (all 3/C). 8.3 Mycophenolic acid, cyclophosphamide, leflunomide and methotrexate should be avoided. [/table]