counseling women with systemic lupus … (possible for all patients including those positive for apl...

27

Review

ISSN 1758-427210.2217/IJR.12.78 © 2013 Future Medicine Ltd Int. J. Clin. Rheumatol. (2013) 8(1), 27–37

Planning a pregnancySystemic lupus erythematosus (SLE) is a systemic autoimmune disorder that preferentially affects women. The peak incidence of SLE is between 20 and 35 years. The disease spectrum spans from few and mild symptoms to multiple and severe organ manifestations that may be life threatening [1]. With improved diagnosis and therapy, as well as improved monitoring of complications during pregnancy, a larger proportion of SLE patients consider having children. It is widely accepted that SLE pregnancies are high risk and should be planned [2], therefore, counseling of patients who desire children is necessary. However, information on family planning should not be given exclusively to patients who ask for it, but should be offered actively to all patients of fertile age. Unplanned pregnancies in a potentially serious disease may threaten both maternal and fetal pregnancy outcome and should be avoided. Patients most at need for prepregnancy counseling may miss important information because they do not ask for advice. This is particularly true for adolescents with juvenile onset of SLE (JSLE). A study of 298 Brazilian JSLE patients found that unplanned pregnancies occurred in 8% with a mean age of 18 years at the first pregnancy [3]. Ten of the patients were younger than 18 years at their first pregnancy.

Counseling should be offered even to patients who are not living in a partnership or who already have children provided they are in the age group of 18–45 years. Partners not present

at a first consultation may appear at a later stage, and partnerships may break up and new ones form so that patients may wish for children with a new partner even when they already have children.

Planning a pregnancy means finding the right time and the right condition for pregnancy. Conception should occur at a stage of remission or minimal disease activity and on stable medication allowing time for adjustment of therapy to drugs compatible with pregnancy. Planning a pregnancy therefore requires counseling on birth control.

Contraception Counseling on birth control is the only way to prevent unplanned and ill-timed pregnancy. It is the responsibility of the treating rheumatologist to address contraception actively in all patients with risk of adverse pregnancy outcome. Situations that involve risk are early stage of disease, active SLE, severe organ manifestations or organ damage, antiphospholipid syndrome (APS) and therapy with possible fetotoxic drugs [4]. No prescription for methotrexate, mycophenolate mofetil or cyclophosphamide should be given without excluding pregnancy and ensuring that comprehensive information on safe birth control has been given. Patients with active disease and a wish for children should practice effective birth control until the disease has improved or has gone into remission for at least 6 months.

With the improvement of diagnosis and therapy, as well as advances in obstetric medicine, a large proportion of female systemic lupus erythematosus patients desire children and demand prepregnancy counseling. Planning a pregnancy means finding the right time and right conditions with low disease activity and therapy adjusted to pregnancy-compatible drugs. Counseling on birth control is necessary to avoid unplanned pregnancies, which carry high maternal and fetal risks. Prenatal counseling requires risk assessment regarding possible maternal or fetal risks, screening for biomarkers with predictive value for adverse pregnancy outcomes, adjustment of therapy and a schedule for monitoring and follow-up during pregnancy. Complications such as lupus nephritis, presence of antiphospholipid antibodies and risk of neonatal lupus syndromes require special attention.

KEYWORDS: antiphospholipid antibody n birth control n drugs during pregnancy n fertility n lupus nephritis n neonatal lupus syndrome n pregnancy n risk assessment n systemic lupus erythematosus

Monika ØstensenNational Center of Pregnancy & Rheumatic Disease, Department of Rheumatology, University Hospital of Trondheim, Trondheim, Norway Tel: +47 81555850 [email protected]

Counseling women with systemic lupus erythematosus who desire children

part of

Int. J. Clin. Rheumatol. (2013) 8(1)28 future science group

Counseling women with systemic lupus erythematosus who desire children ReviewReview Østensen

Several studies have shown that contraceptive counseling is an ‘often forgotten duty’ [4–6]. An investigation among 206 female SLE patients, found 86 women were at risk for unplanned pregnancy, but only 41% had received contraceptive counseling in the last year [6]. Women treated with potentially teratogenic medications or positive for antiphospholipid antibodies (aPL) were no more likely to have received contraceptive counseling, to have used contraception consistently or to have used more effective contraceptives. More than half of the patients depended solely on barrier methods. One-fifth of the patients reported inconsistent contraceptive use, and several women with a history of thrombosis or aPL used estrogen- containing hormonal contraceptives [6]. In the Brazilian study of JSLE, four women conceived while receiving intravenous cyclophosphamide pulses [3]. Even when patients are informed about possible teratogenic risks of therapy, adherence to the advice given may fail. A survey of patients with inflammatory arthritis showed that correct advice regarding fetotoxicity of immunosuppressive drugs had been given to 84% of female patients; however, one-third of them did not practice contraception [5]. Reasons for noncompliance are multiple and include misunderstandings, forgetfulness, reluctance to

have yet another drug to take and failure of the physician to repeat information.

Counseling on safe birth control means explaining in detail which contraceptive methods actually prevent an unintended pregnancy [7]. Natural and barrier methods are highly unreliable and only hormonal contraceptives, intrauterine devices (IUDs) and sterilization have acceptable efficacy with low failure rates (Table 1) [4]. Young patients should be informed about emergency contraception.

However, women with SLE may have contraindications against combined oral contraceptives (COCs) containing estrogen. Several studies in the 1980s showed COCs with doses of estrogen varying from 35 to 50 mg could induce flares in some lupus patients [8]. Two studies showed that COCs do not increase flares in women with established SLE that is inactive or only moderately active and where aPL are not present [9,10]. In a placebo-controlled study of 183 SLE women, patients receiving COCs containing 35 µg of ethinyl estradiol had a similar 12-month flare rate as those receiving placebo [9]. In the second study of different birth control methods in 162 women with SLE, no difference in the 12-month flare rate was found for COCs, a progestin-only pill or a copper IUD. Thrombosis was rare and

Table 1. Safe birth control (failure rate 0.3–8.0% at typical use) recommended for different types of systemic lupus erythematosus patients.

Method of birth control Safety–failure rate at perfect/typical use (%)

Recommended for patients with characteristics

Combined hormonal contraception containing estrogen plus progestin (for patients with mild/moderate and stable disease activity, no aPL, no APS)

Combined oral contraceptives containing 15–35 µg estrogen

0.3–8.0 All ages of premenopausal SLE patients

Hormonal patch 0.3–8.0 Patients who do not want another pill

Vaginal ring 0.3–8.0 Patients who do not want another pill

Progestin only (for patients positive for aPL or with APS; patients with very active and severe SLE)

Progestin-only pills 0.5–8.0 Patients who have good compliance

Implant 0.1 Patients who do not want another pill or with poor compliance

Injection of medroxyprogesterone 0.3 Patients with poor complianceBe aware of amenorrhea and osteoporosis

IUD (possible for all patients including those positive for aPL or with APS, or with active and severe SLE)

Copper IUD 0.1–0.8 Patients who do not want another pill or with poor compliance Patients dependent on low cost of birth control

Levonorgestrel IUD 0.1–0.8 All patients, particularly suited for patients on anticoagulation

Sterilization

Female sterilization 0.1 Reserve for women who have completed their families

aPL: Antiphospholipid antibodies; APS: Antiphospholipid syndrome; IUD: Intrauterine device; SLE: Systemic lupus erythematosus. Reproduced with permission from [4].

www.futuremedicine.com 29future science group


occurred only in women positive for aPL and on hormonal contraception [10]. The results show that premenopausal SLE patients with minimal or moderate disease activity and who lack aPL may use COCs.

SLE patients with persistent medium or high titers of aPL or with APS should not use COCs, but receive progestagens only, either perorally or by gestagen containing devices such as a progestin implant or injections [7]. IUDs are also an option. Gestagen containing IUDs are particularly suited for women with APS who are on anticoagulation [11].

FertilityPatients with SLE are sometimes concerned about fertility because of either the disease process or because of treatment with cyclophosphamide (CYC). Several studies have shown that fertility is reduced in SLE compared with healthy women [12–14], and the reason is multifactorial. Active disease, recurrent pregnancy losses, aPL and autoantibodies against ovarian tissue or sperm, reduced ovarian reserve as well as a deliberate choice to limit family size play a role [15]. A recent study found that fertility defined as pregnancies achieved was 2.0–2.4 pregnancy per SLE patient, not different from healthy women. However, due to increased pregnancy loss, women with lupus do have fewer children than they desire [15]. In the past, treatment with CYC has been a major reason for infertility in women with severe lupus [16,17]. New therapies such as mycophenolate mofetil or B-cell inhibitors are not gonadotoxic; however, at present, treatment protocols for acute and severe lupus still include CYC, although at a much reduced total dose (3 g of CYC in the Eurolupus protocol) [18]. Occurrence of premature ovarian failure (POF) induced by CYC is related to the cumulative dose of CYC and the age of the patient with the greatest risk of POF in women of 30 years and over [16]. Counselling on fertility preservation is, therefore, mandatory in all SLE patients who start on a therapy with CYC. There are a number of methods available with the use of gonadotropin-releasing hormone (GnRH) agonists being one of the most promising [19,20]. Referral to a gynecologist experienced in reproductive medicine or an infertility clinic for treatment recommendations is important since not all methods are suited for SLE patients.

Risk assessmentRisk assessment in regard to possible maternal or fetal risks during a future pregnancy is essential

for counseling an individual patient and adjusting therapy [21]. Major maternal risks are active disease at conception [22,23], a flare during pregnancy, conception during a stage of active organ involvement or severe organ damage, presence of aPL and antibodies against SS-A (Ro) and SS-B (La) [21–24]. A clinical work-up and laboratory tests will show the presence of risk factors for a future pregnancy, and will allow a stratification into a high-, moderate- or low-risk profile. Therapy adjustment as well as type and frequency of monitoring will relate to the risk profile in the individual patient. Patients with severe involvement of lungs or heart including symptomatic pulmonary hypertension, extensive restrictive lung disease and cardiomyopathy, as well as women with previous HELLP syndrome, should be discouraged from pregnancy because of increased morbidity and mortality [21,24,25]. Patients with recent arterial thrombosis or current active renal disease should postpone pregnancy [21].

Flare during pregnancyA major maternal risk for the mother is a lupus flare during pregnancy [26]. Women with current or recent activity at the time of conception and those who withdraw hydroxychloroquine are more likely to suffer a disease flare [21,26,27]. The risk for a severe flare increases seven times in the case of lupus activity at conception [28]. Pregnancies occurring during or shortly after a period of active lupus have significantly worse outcomes than pregnancies taking place in a state of remission [21–23]. Two population-based studies comparing pregnancy outcomes in SLE patients with healthy women in the USA found the risk for maternal morbidity and mortality increased two- to four-fold in lupus patients [28,29]. Case–control studies have shown that lupus flares during pregnancy are fairly common with a frequency of more than 57% and flare rates ranging from 0.06 to 0.136 per patients per month [26,30–35]. Musculoskeletal, mucocutaneous and hematological flares are the most likely to occur with a frequency of approximately 75%, whereas only 15–30% of pregnant patients suffer from severe complications of SLE during pregnancy [31,33,34]. It is important to consider that physiological changes in pregnancy, such as joint pain, rash and fatigue can be mistaken for disease activity. Mild anemia, mild thrombocytopenia and mild proteinuria can also occur in normal pregnancy. Prevention of a flare during pregnancy includes conception in a state of remission, supportive



drug therapy and close monitoring (Table 2) [26]. The importance of a prolonged period of quiescent disease before conception, as well as the continuation of antimalarials, must be explained to the patient [35].

Lupus nephritisA meta-analysis of 2751 SLE pregnancies found a significant correlation between fetal loss, hypertension, pre-eclampsia and premature delivery in patients with past or present lupus nephritis [36]. Proteinuria >1 g, reduced GFR and aPL in addition to lupus nephritis increase the risk for adverse pregnancy outcomes [36–38]. Predictors for a flare of lupus nephritis are active renal disease at conception, hypertension and a creatinine level of 140 µmol/l or more [24,38].

Several studies have investigated the long-term effect of pregnancy on renal function in patients with lupus nephritis. SLE patients with baseline serum creatinine levels higher than 2.5–2.8 mg dl, (220–250 µmol/l) are most likely to suffer postpartum renal function decline, as well as complications during pregnancy [36–38]. By contrast, patients with previous nephritis, but in remission with normal renal function and blood pressure at conception, have no increased risk for deterioration of renal function during or after pregnancy. This was shown in a study comparing the pregnancies of 64 SLE patients without and 43 SLE patients with lupus nephritis [39]. No significant deterioration of renal function occurred in either group during a follow-up of, on average, 3 years. Another cohort study compared pregnant SLE patients with lupus nephritis to nonpregnant SLE patients with lupus nephritis without finding any significant difference in renal function [40].

Based on these new data, a woman with previous lupus nephritis and normal or slightly reduced renal function can be assured that pregnancy occurring in a quiescent state of SLE carries no increased risk for progression of renal disease, although the risk for pre-eclampsia is still increased [38].

Fetal risksPregnancies in women with SLE are character-ized by an increased incidence of abortions and stillbirths, prematurity and intrauterine growth restriction (IUGR) [28,29,36]. The rate of fetal loss has been found to be in the range of 11–29%, and is 1.5–2.5-times more prevalent than in the normal population [28,41]. The risk of adverse outcomes also remains high in studies during the period from 2000 to 2009, as reported in a population-based study of SLE pregnancies showing an increased risk of prematurity (OR: 2.92), as well as perinatal deaths (OR: 3.59) [42]. Active lupus nephritis, previous history of fetal death and the presence of aPL have been shown to be predictive factors for fetal loss in lupus pregnancies [35,36]. A study of 265 pregnancies found that active SLE in the 3 months prior to conception corresponded with a fourfold increase in pregnancy loss [22].

Preterm birth (delivery at <37 weeks of gestation) is one of the most common adverse outcomes of lupus pregnancies related to multiple risk factors such as active lupus, high dose (>20–15 mg) of corticosteroids, renal disease, thyroid disease [42], aPL, hypertension, pre-eclampsia, premature rupture of the membranes and fetal compromise [22,24,28,29,36]. The same factors increase the risk of IUGR, reported to be 8–29% [28,35,36], and small for gestational age (SGA) infants [43].

Table 2. Adjustment of drug therapy and lifestyle before conception.

Discontinue before conception

Continue during pregnancy when indicated

Start with

MethotrexateCyclophosphamide RituximabBelimumabTocilizumabMycophenolate mofetil Angiotensin-converting enzyme inhibitorsBisphosphonatesCoumarin derivates

AntimalarialsPrednisoneAzathioprineCyclosporineTacrolimus

Low-molecular weight heparin

Folic acidVitamin D plus calciumAspirin for prevention of pre-eclampsia

Switch from coumarin derivates to low-molecular weight heparin

NicotineAlcoholRecreational drugs

Healthy diet containing multiple vitamins



Patients with SLE planning a pregnancy should be informed about the increased risk of adverse fetal outcomes in a way that is not frightening, but supports adherence to frequent monitoring and necessary therapy. Even when therapy can reduce pregnancy complications and adverse outcomes, it cannot guarantee their complete prevention. The physician should be particularly alert to the risk of pregnancy loss in women who begin pregnancy with proteinuria, APS, thrombocytopenia and hypertension [41].

Women with SLE are sometimes concerned about the outcome of a subsequent pregnancy, particularly in the case of an adverse previous pregnancy outcome. The chance for a better outcome is present in the case of a previous perinatal death [43], although the risk for miscarriage and pregnancy complications still remains. In general, pregnancy outcomes in lupus patients have improved [44], but the risk of recurrence of pre-eclampsia, prematurity and SGA infants is present in subsequent pregnancies [45].

Antibodies In total, 30–50% of SLE patients have aPL, but only one-third show the clinical picture of the APS with obstetric or thrombotic events [1]. Presence of significant and repeated positive titers of aPL increase the risk for adverse pregnancy outcomes comprising unexplained spontaneous abortions before 10 weeks of gestation, intrauterine fetal death and one or more premature births of a morphologically normal neonate before 34 weeks of gestation [46]. Women with aPL are in general at a higher risk for hypertension, pre-eclampsia, fetal death, placental insufficiency with growth restriction and prematurity [36,47–49]. Some studies found combined positivity for lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) and anti-ß2-glycoprotein I as the most significant risk factor [50,51], whereas a recent study of 144 SLE and APS pregnancies found only LAC as a strong predictor for adverse pregnancy outcomes [52].

In addition to the known obstetric comp-lications of the APS, a risk of microangiopathic antiphospholipid-associated syndromes (MAPSs), including HELLP syndrome and renal microangiopathy, are also present [53,54]. SLE patients with APS and previous arterial or venous thrombosis, especially those who have suffered a stroke, are at risk for recurrent thrombosis during pregnancy [51]. Even women with only obstetric manifestations of APS have an increased risk of thrombosis as shown

by a study of 57 APS patients with recurrent miscarriages [55]. Whether asymptomatic carriers of aPL are at an increased risk of pregnancy pathology or thrombosis has not been clarified.

Neonatal lupus erythematosus Presence of maternal antibodies to the 52 kD SSA/Ro, 60 kD SSA/Ro or 48 kD SSB/La ribonucleoproteins predispose to the development of neonatal lupus erythematosus (NLE). NLE manifests either as transient cutaneous lupus lesions, cytopenia and hepatic dysfunction, or cardiac manifestations including conduction defects, cardiomyopathy and congestive heart failure [56,57]. Congenital heart block (CHB) is the only permanent manifestation with an increased morbidity and mortality of the affected child [57]. A prospective study showed a 2% prevalence of CHB in newborns of women with connective tissue disease and SSA/Ro antibodies [58]. The highest risk of CHB has been observed with positive anti-52 kD SSA, (OR: 18.9) and is clearly related to the titer of autoantibodies [59,60]. The vulnerable period for development of cardiac manifestations is between 16 and 24 weeks of gestation with weekly echocardigraphic monitoring of fetal cardiac function recommended (Table 2) [57,61]. Maternal treatment with b-methasone or dexamethasone is a choice for milder conduction defects such as sinus bradycardi, prolongation of Q-T interval or a first-degree AV block whereas a third-degree AV block is irreversible [62,63]. The lupus patient with significant titers of anti-Ro/anti-La antibodies must be informed about the necessity of regular monitoring of fetal heart function during pregnancy. Should the patient have a previous child with CHB, the recurrence risk of CHB has been estimated to be 12–19% [64]. Furthermore, cutaneous NLE increases the risk for CHB six- to ten-fold in a subsequent pregnancy [65]. A regular follow-up of children born with a prolongation of the Q-T interval or a first-degree block through the first 3 years should also be recommended.

Adjustment of drug therapy Women who plan a pregnancy often stop taking medications out of fear of harming the fetus, especially in the first trimester. Withdrawal of effective therapy in SLE may lead to aggravation of disease activity, with adverse effects on both the mother and fetus. Adjustment of medication must therefore be discussed in good time with patients desiring children, so an ill-timed stop of therapy can be avoided (Table 2). Comprehensive



information on the effects and side effects of immunosuppressive drugs and their safety during pregnancy should help the patient to understand that effective disease control during pregnancy is important for a normal pregnancy course and for child health. She should also be reassured about the possibility of controlling a flare of SLE during pregnancy. For severe lupus f lares, short-term high-dose corticosteroids or the use of drugs contraindicated during pregnancy may sometimes be necessary (Table 3). Some drugs are discussed in more detail below.

Antimalarial drugs (AM), chloroquine (CQ) and hydroxychloroquine (HCQ) are the mainstay of treatment in SLE patients. They exert not only immunmodulating effects, but have a number of positive effects that are particularly beneficial for SLE patients [66,67]. These include prevention of lupus f lares, lowering of lipid levels and moderate protection against thrombosis [67]. Studies of pregnant SLE patients have shown that the risk of a flare during pregnancy is reduced in women continuing with AM throughout pregnancy [26,35]. All studies investigating neonatal outcomes after in utero exposure to AM found no increase in birth defects and no ocular, auditory, neurological or cardiac toxicity in the newborn [68]. A recent study gave the indication that continuation of antimalarials during pregnancy even reduced the frequency of congenital heart block in children of mothers positive for anti-Ro/anti-La

antibodies [69]. A proportion of children exposed prenatally to antimalarials had follow-ups until an average of 4 years without showing any sign of adverse long-term effects [70].

�n CorticosteroidsA majority of SLE patients receive prednisone or prednisolone either in low dose (<15 mg/day) for mild symptoms or for treatment of flares in doses exceeding 20 mg/day. A meta-analysis of epidemiological studies including pregnant patients with different autoimmune and allergic diseases found a slight, although significant, increase of oral clefts after first trimester exposure to corticosteroids [71]. Overall, the risk of oral clefts is low [72]. Corticosteroids, except for fluorinated compounds, are partly inactivated by 11-b-hydroxylases of the placenta with relative protection of the fetus. In late pregnancy, doses of corticosteroids exceeding 20 mg/day can cause IUGR and preterm delivery, and increase the frequency of maternal side effects such as hypertension, diabetes mellitus and osteoporosis [73]. However, severe lupus flares during pregnancy most often need high-dose corticosteroids for rapid control of symptoms.

�n AzathioprineAccumulated data from transplant centers in North America and Europe on pregnancies in allograft recipients treated with corticosteroids and azathioprine found no increase in birth

Table 3. Therapy and monitoring of lupus complications during pregnancy.

Complication Type of complication Drugs compatible in case of pregnancy complication

Monitoring during pregnancy

Active disease during pregnancy

Lupus dermatitisActive arthritis during pregnancy

Antimalarials, prednisone, NSAIDs (discontinue at week 32)ParacetamolIntra-articular corticosteroids

Clinical and laboratory assessment at all visitsSerial ultrasonography

Active disease during pregnancy

Lupus nephritis or other organ manifestation

Antimalarials, prednisoneAzathioprineCyclosporine, tacrolimusIntravenous immunoglobulin

Clinical and laboratory assessment at all visits, Doppler studies of uterine arteries between week 20 and 24

Antiphospholipid syndrome

APS previous fetal lossAPS previous thrombosis

Low-dose aspirin alone or plus LMWH (INR: 2–3)Low-dose aspirin plus LMWH (INR: 2–3, arterial thrombosis INR: 3–4)

Clinical and laboratory assessment at all visits, Doppler studies of uterine arteries between week 20 and 24

Cardiac Hypertension Antihypertensive such as methyldopa,nifedipine, atenolol

Control of blood pressure throughout pregnancy, Doppler studies of uterine arteries between week 20 and 24

Antibodies SS-A/SS-B 1 or 2 degree AV-blockMyocarditis, ascites, hydrops fetalis

Preferentially b-methasone, dexamethasone (more side effects for child)

Fetal echocardiography weekly between week 16 and 24, biweekly thereafter

APS: Antiphospholipid syndrome; AV: Atrioventricular; INR: International Normalized Ratio; LMWH: Low-molecular weight heparin.



defects [68,74,75]. Case–control and cohort studies of pregnancies in SLE and inflammatory bowel disease showed that azathioprine controlled disease activity, reduced the rate of pregnancy losses and did not increase congenital malformations [26,75]. Doses of azathioprine during pregnancy should be kept at 1.5–2 mg/kg/day to avoid neonatal depression of hematopoiesis [76].

�n Mycophenolate mofetil Mycophenolate mofetil (MMF) blocks purine synthesis in T and B cells and is used successfully in the treatment of lupus nephritis. Animal and human studies showed teratogenicity of MMF with a special phenotype in newborns after MMF antenatal exposure including microtia, auditory canal atresia, cleft lip and palate, micrognathia, hypertelorism, ocular coloboma, short fingers and hypoplastic nails [77]. The risk of first trimester exposure to MMF is approximately 26% [77]. Patients who start treatment must be informed that discontinuation of MMF is necessary at least 6 weeks before trying to conceive, and be advised to use effective birth control. Patients with a history of lupus nephritis who are on maintenance therapy with MMF should be switched to azathioprine.

Among immunosuppressive drugs to be discontinued before conception are known teratogens such as CYC and methotrexate (MTX), and agents for which safety during pregnancy is not or insufficiently known [68]. The latter includes rituximab (few case reports on SLE pregnancies) and belimumab (no published experience; Table 3) [78]. Therapy with CYC or MTX requires safe contraception. Attempts to conceive should be delayed until 3 months after the cessation of therapy.

Hypertension is frequent in SLE patients, often related to renal disease. Patients receiving therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers must stop these drugs before a planned pregnancy owing to their teratogenic potential (Table 3) [79].

Women with consistent moderate-to-high levels of aPL or APS must be informed about the risk of thrombosis, pregnancy loss and pre-eclampsia, as well as the necessity of anticoagulation during pregnancy and post-partum [21]. The choice of treatment depends on whether aPL alone or additional symptoms typical of the APS are present. Therapy options for subtypes of aPL-positive women have been

discussed in detail in previous reviews [21,80,81]. Patients treated for APS with coumarine derivates must discontinue them before conception and switch to low-molecular weight heparin [81].

Control during pregnancyType and frequency of controls during pregnancy should be agreed upon with the patient and contacts established between doctors involved in follow-up. Frequent monitoring during pregnancy by a specialist team including a rheumatologist/specialist in internal medicine, obstetrician and specialist in fetal medicine increases the chance of a successful pregnancy. The schedule for controls depends on the severity of SLE and maternal and fetal risk factors present at conception. Monthly controls may be sufficient during the first trimester in patients in remission, but intervals of 2 or 3 weeks are required later on. Active disease demands frequent controls once weekly. The differences observed in the rate of adverse pregnancy outcomes reported from different countries are influenced by the type of healthcare available, access to methods of contraception, high-risk pregnancy units and coverage of costs by insurance companies or governmental institutions. It appears that child outcomes depend on the quality of prenatal care [82]. Access to optimal healthcare may not be available for patients living in rural areas or patients of low socio-economic status, therefore a substantial risk of adverse pregnancy outcomes remains for a large proportion of patients.

General recommendationsLifestyle adjustments before pregnancy include stopping smoking, using no alcohol or recreational drugs during pregnancy and maintaining a healthy diet containing multiple vitamins [83]. The importance of folic acid supplementation during the early stages of pregnancy needs to be emphasized [84]. The usual dose for healthy pregnant women, as well as SLE patients, is 0.4 mg/day. Patients who have received therapy with MTX previously should continue 1 mg daily before conception and at least throughout the first trimester.

Several studies have shown insufficient or deficient levels of vitamin D in lupus patients as well as in a substantial proportion of pregnant women [85]. Use of sun-blocking agents because of photosensitive rash, therapy with corticosteroids and renal disease may contribute to vitamin D deficiency in SLE patients. Vitamin D has immunmodulating properties



and low levels of vitamin D are associated with more severe disease in SLE [86]. Levels of 25 OHD should be measured before or early in pregnancy and substitution be given in SLE patients with low levels of vitamin D.

Since pre-eclampsia and preterm birth are frequent events in SLE patients, reduction of the increased risk should be considered by treatment with low-dose aspirin throughout gestation [87].

Conclusion The prospects of a successful pregnancy in SLE have greatly improved during the last two decades. However, specific disease-related pathology and active disease still render lupus pregnancies high risk for mother and child. Because of the inherent risks, lupus pregnancies should be planned and not occur unexpectedly. Advice on contraception is, therefore, indispensable for the right timing of pregnancy and should be given to all patients of fertile age, particularly to adolescents with SLE. Prepregnancy counseling means to prepare patients desiring children for adequate monitoring and management during pregnancy. Proper assessment of maternal and

fetal/neonatal risks and psychological skill to confer necessary information without causing undue anxiety are required. Well-informed patients can collaborate to achieve healthy pregnancy outcomes.

Future perspective Future aims for the reduction of pregnancy complications and improving pregnancy outcomes in SLE patients include the identification of early biomarkers revealing clinically quiescent inflammation and factors that trigger damage to the maternal–fetal unit. Several angiogenic/antiangiogenic proteins have been shown to be markers for development of pre-eclampsia; however, the tests are still insufficient for accurate prediction of this event [88]. Other factors of importance are biomarkers that can distinguish pre-eclampsia from a flare of lupus nephritis and biomarkers for preterm delivery. Identification of reliable markers would help to diagnose adverse events at an early stage and to prevent them by targeted therapy. In regard to therapy during pregnancy, more studies on rituximab and new studies on belimumab are

Executive summary

Planning a pregnancy

� Information on family planning should be actively offered to all patients of fertile age. Unplanned pregnancies can impair both maternal and fetal pregnancy outcomes.

� Conception should occur at a stage of remission or minimal disease activity and on stable medication that is compatible with pregnancy.

Contraception

� Contraception counseling is the way to avoid unplanned pregnancies, and should be given to all patients treated with potentially teratogenic drugs, those with recently active lupus and patients with severe organ damage.

Fertility preservation

� Discussion of fertility preservation methods is necessary for patients of childbearing age who start therapy with cyclophosphamide.

Risk stratification

� Assessment of maternal and fetal risks by a clinical and laboratory work-up is a prerequisite for preconceptional counseling.

Prevention of a flare

� Prevention of a flare during pregnancy includes conception in a state of remission, supportive drug therapy and close monitoring during pregnancy.

Predictors for fetal loss

� Active disease, lupus nephritis, high-dose corticosteroids, previous history of fetal death and the presence of antiphospholipid antibodies are predictors for fetal loss in lupus pregnancies.

Autoantibodies with impact on pregnancy outcome

� SLE patients with antiphospholipid antibodies and/or antiphospholipid syndrome are in general at a higher risk for hypertension, pre-eclampsia, fetal death, placental insufficiency with growth restriction and prematurity.

� Maternal antibodies to the 52 kD SSA/Ro, 60 kD SSA/Ro or 48 kD SSB/La ribonucleoproteins predispose to the development of neonatal lupus syndromes and require close monitoring during pregnancy in order to detect congenital heart block.

Adjustement of drug therapy

� Drug therapy and lifestyle factors must be reviewed preconceptionally and be adjusted to the benefit of pregnancy.

Monitoring during pregnancy

� Controls during pregnancy should be scheduled according to the patient’s disease activity and the presence of risk factors.



needed to investigate their safety for the fetus and newborn.

Financial & competing interests disclosureM Østensen has received speaker fees from Mepha, MSD, Pfizer, Roche and UCB, Inc. The author has no other

relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-cial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

ReferencesPapers of special note have been highlighted as:n of interestnn of considerable interest

1 Cervera R, Khamashta MA, Shoenfeld Y, et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann. Rheum. Dis. 68, 1428–1432 (2009).

2 Lê Huong D, Wechsler B, Vauthier-Brouzes D et al. Outcome of planned pregnancies in systemic lupus erythematosus: a prospective study on 62 pregnancies. Br. J. Rheumatol. 36, 772–777 (1997)

3 Silva CAA, Hilario MO, Febronio MV et al. Pregnancy outcome in juvenile systemic lupus erythematosus: a Brazilian multicenter cohort study. J. Rheumatol. 35, 1414–1418 (2008)

4 Østensen M. Connective tissue diseases: contraception counseling in SLE – an often forgotten duty? Nat. Rev. Rheumatol. 7, 315–316 (2011).

5 Østensen M, von Esebeck M, Villiger PM. Therapy with immunosuppressive drugs and biological agents and use of contraception in patients with rheumatic disease. J. Rheumatol. 34, 1266–1269 (2007).

6 Yazdany J, Trupin L, Kaiser R et al. Contraceptive counseling and use among women with systemic lupus erythematosus: a gap in healthcare quality? Arthritis Care Res. 63, 358–365 (2011).

7 Sammaritano LR. Therapy insight: guidelines for selection of contraception in women with rheumatic diseases. Nat. Clin. Pract. Rheum. 3, 273–281 (2007).

nn� Systematic overview of birth control methods showing that there is a suitable method for all, also includes recommendations for women with estrogen intolerance or other risk factors.

8 Bernier MO, Mikaeloff Y, Hudson M, Suissa S. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum. 61, 476–481 (2009).

9 Petri M, Kim MY, Kalunian KC et al. Combined oral contraceptives in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 2550–2558 (2005).

10 Sánchez-Guerrero J, Uribe AG, Jiménez-Santana L et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 3539–3549 (2005).

11 Pisoni CN, Cuadrado MJ, Khamashta MA, Hunt BJ. Treatment of menorrhagia associated with oral anticoagulation: efficacy and safety of the levonorgestrel releasing intrauterine device (Mirena coil). Lupus 15, 877–880 (2006).

12 Pasoto SG, Mendonca BB, Bonfa E. Menstrual disturbances in patients with systemic lupus erythematosus without alkylating therapy: clinical, hormonal and therapeutic associations. Lupus 11, 175–180 (2002).

13 Lawrenz B, Henes J, Henes M et al. Impact of systemic lupus erythematosus on ovarian reserve in premenopausal women: evaluation by using anti-Muellerian hormone. Lupus 20, 1193–1197 (2011).

14 Vinet E, Labrecque J, Pineau CA et al. A population-based assessment of live births in women with systemic lupus erythematosus. Ann. Rheum. Dis. 71(4), 557–559 (2012).

15 Clowse M, Chakravarty E, Costenbader KH, Chambers C, Michaud K. Effects of infertility, pregnancy loss and patients concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. 64(5), 668–674 (2012).

n� Survey of 578 rheumatoid arthritis (RA) and 114 systemic lupus erythematosus women showed that 55% with RA and 64% with systemic lupus erythematosus had fewer children than originally planned. In RA this was due to infertility; in systemic lupus erythematosus due to increased pregnancy loss.

16 Boumpas DT,Austin HA,Vaughan EM,Yarboro CH, Klippel JH, Balow JE. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann. Intern. Med. 119, 366–369 (1993).

17 Clowse ME, Copland SC, Hsieh TC et al. WGET Research Group: ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener’s). Arthritis Care Res. 63, 1777–1781 (2011).

18 D’Cruz DP, Houssiau FA. The Euro-Lupus Nephritis Trial: the development of the sequential treatment protocol. Lupus 18(10), 875–877 (2009).

19 Silva CA, Bonfa E, Ostensen M. Maintenance of fertility in patients with rheumatic diseases needing anti-inflammatory and immunosuppressive drugs. Arthritis Care Res. 62, 1682–1690 (2010).

20 Henes M, Henes J, Neunhoeffer E et al. Fertility preservation methods in young women with systemic lupus erythematosus prior to cytotoxic therapy: experiences from the FertiProtekt network. Lupus 21(9), 953–958 (2012).

n� Majority of 68 systemic lupus erythematosus patients counseled for fertility preservation during treatment with cyclophosphamide decided on protective treatment with gonadotropin-releasing hormone, although other methods such as cryoconservation of ovarian tissue and of fertilized eggs were also chosen.

21 Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy: integrating clues from the bench and bedside. Eur. J. Clin. Invest. 41(6), 672e8 (2011).

22 Clowse M, Magder LS, Witter F, Petri M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 52(2), 514–521 (2005).

nn� Prospective study of 267 lupus pregnancies showed that high disease activity significantly increased adverse pregnancy outcomes compared with low disease activity.

23 Ko HS, Ahn HY, Jang DG et al. Pregnancy outcomes and appropriate timing of pregnancy in 183 pregnancies in Korean patients with SLE. Int. J. Med. Sci. 8(7), 577–583 (2011).

24 Kwok LW, Tam LS, Zhu TY, Leung YY, Li EK. Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus 20, 829–836 (2011).

25 Chakravarty EF, Khanna D, Chung L. Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension and sickle cell disease. Obstet. Gynecol. 111(4), 927–934 (2008).

26 Stojan G, Baer AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and



management. Expert Rev. Clin. Immunol. 8(5), 439–453 (2012).

27 Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 54(11), 3640–3647 (2006).

28 Clowse ME, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. Am. J. Obstet. Gynecol. 199(2), 127 e1–e6 (2008).

nn� Pregnant systemic lupus erythematosus patients showed a three- to seven-fold increase in maternal complications and adverse pregnancy outcomes compared with healthy women.

29 Yasmeen S, Wilkins EE, Field NT, Sheikh RA, Gilbert WM. Pregnancy outcomes in women with systemic lupus erythematosus. J. Matern. Fetal Med. 10(2), 91–96 (2001).

30 Lockshin MD, Reinitz E, Druzin ML et al. Lupus pregnancy. Case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am. J. Med. 77, 893–898 (1984).

31 Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis Rheum. 34, 1538–1545 (1991).

32 Tincani A, Faden D, Tarantini M et al. Systemic lupus erythematosus and pregnancy: a prospective study. Clin. Exp. Rheumatol. 10, 439–446 (1992).

33 Ruiz-Irastorza G, Lima F, Alves J et al. Increased rate of lupus flare during pregnancy and the puerperium. Br. J. Rheumatol. 35, 133–135 (1996).

34 Doria A, Cutolo M, Ghirardello A et al. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum. 47, 202–209 (2002).

35 Cortes-Hernandez J, Ordi-Ros J, Paredes F, Casellas M, Castillo F, Vilardell-Tarres M. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) 41, 643–650 (2002).

36 Smyth A, Oliveira GHM, Lahr BD, Bailey KR, Norby SM,Garovic VD. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin. J. Am. Soc. Nephrol. 5(11), 2060–2068 (2010).

nn� Systematic review and meta-analysis of pregnancy outcomes in women with lupus nephritis showing that lupus nephritis and phospholipid antibodies increase the risk of maternal hypertension and premature birth.

37 Imbasciati E, Tincani A, Gregorini G et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal

outcome. Nephrol. Dial. Transplant. 24, 519–525 (2009).

38 Germain S, Nelson-Piercy C. Lupus nephritis and renal disease in pregnancy. Lupus 15, 148–155 (2006).

39 Bramham K, Hunt BJ, Bewley S et al. Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis. J. Rheumatol. 38(9), 1906–1913 (2011).

40 Tandon A, Ibanez D, Gladman DD, Urowitz MB. The effect of pregnancy on lupus nephritis. Arthritis Rheum. 50, 3941–3946 (2004).

41 Clowse ME, Magder LS, Witter F, Petri M. Early risk factors for pregnancy loss in lupus. Obstet. Gynecol. 107(2 Pt 1), 293–299 (2006).

42 Stagnaro-Green A, Akhter E, Yim C, Davies TF, Magder L, Petri M. Thyroid disease in pregnant women with systemic lupus erythematosus: increased preterm delivery. Lupus 20(7), 690–699 (2011).

43 Shand AW, Algert CS, March L, Roberts CL. Second pregnancy outcomes for women with systemic lupus erythematosus. Ann. Rheum. Dis. doi:10.1136/annrheumdis-2011-201210 (2012) (Epub ahead of print).

44 Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients withsystemic lupus erythematosus over a 40-year period. J. Rheumatol. 32, 1709–1712 (2005).

45 Skomsvoll JF, Baste V, Irgens LM, Østensen M. The recurrence risk of adverse outcome in the second pregnancy in women with rheumatic disease. Obstet. Gynecol. 100, 1196–2002 (2002).

46 Miyakis S, Lockshin MD, T. Atsumi et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Hemost. 4(2), 295–306 (2006).

47 Nodler J, Moolamalla SR, Ledger EM, Nuwayhid BS, Mulla ZD. Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset. BMC Pregnancy Childbirth 9, 11–31 (2009).

48 Yamada H, Atsumi T, Kobashi G et al. Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes. J. Reprod. Immunol. 79, 188–195 (2009).

49 Ruffatti A, Calligaro A, Hoxha A et al. Laboratory and clinical features of pregnant women with antiphospholipid syndrome and neonatal outcome. Arthritis Care Res. 62, 302–307 (2010).

50 Ruffatti A, Tonello M, Cavazzana A et al. Laboratory classification categories and

pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy. Thromb. Res. 123, 482–487 (2009).

51 Fischer-Betz R, Specker C, Brinks R, Schneider M. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischemic events: an observational study. Lupus 21(11), 1183–1189 (2012).

52 Lockshin M, Kim M, Laskin CA et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 64(7), 2311–2318 (2012).

53 Asherson RA, Pierangeli S, Cervera R. Microangiopathic antiphospholipid-associated syndromes revisited – new concepts relating to antiphospholipid antibodies and syndromes. J. Rheumatol. 34(9), 1793–1795 (2007).

54 Suzumori N, Obayashi S, Kumagai K, Goto S, Yoshida A, Sugiura-Ogasawara M. A Case of microangiopathic antiphospholipid-associated syndromes during pregnancy: review of the literature. Case Report Med. 8, 275–243 (2012).

55 Martinez-Zamora MA, Peralta S, Creus M et al. Risk of thromboembolic events after recurrent spontaneous abortion in antiphospholipid syndrome: a case–control study. Ann. Rheum. Dis. 71(1), 61–66 (2012).

56 Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin. Rev. Allergy Immunol. 40(1), 27–41 (2011).

57 Buyon, JP, Clancy, RM, Friedman, DM. Cardiac manifestations of neonatal lupus erythematosus: guidelines to management, integrating clues from the bench and bedside. Nat. Clin. Pract. Rheumatol. 5, 139–148 (2009).

58 Brucato A, Frassi M, Franceschini F et al. Congenital heart block risk to newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis. A prospective study of 100 women. Arthritis Rheum. 44, 1832–1835 (2001).

59 Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E. The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus a prospective study of 186 antibody-exposed fetuses and infants. J. Am. Coll. Cardiol. 55, 2778–2784 (2010).

n� Serial screening of 186 fetuses showed that healthy outcomes occurred in 146 children from mothers with low titers of anti-Ro antibodies, whereas cardiac features were



37www.futuremedicine.com

related to moderate-to-high titers of maternal anti-Ro.

60 Reed J, Clancy R, Lee KH, Saxena A, Izmirly PM, Buyon JP. Umbilical cord blood levels of maternal antibodies reactive with p200 and full-length Ro 52 in the assessment of risk for cardiac manifestations of neonatal lupus. Arthritis Care Res. 64(9), 1373–1381 (2012).

61 Friedman DM, Kim MY, Copel JA et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamathasone Evaluation (PRIDE) study. Circulation 117, 485–493 (2008).

62 Rein AJ, Mevorach D, Perles Z, Gavri S, Nadjari M, Nir A, Elchalal U. Early diagnosis and treatment of atrioventricular block in the fetus exposed to maternal anti-SSA/Ro-SSB/La antibodies: a prospective, observational, fetal kinetocardiogram based study. Circulation 119(14), 1867–1872 (2009).

63 Mevorach D, Elchalal U, Rein AJ. Prevention of complete heart block in children of mothers with anti-SSA/Ro and anti-SSB/La autoantibodies: detection and treatment of first-degree atrioventricular block. Curr. Opin. Rheumatol. 21, 478–482 (2009).

64 Llanos C, Izmirly PM, Katholi M et al. Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. Arthritis Rheum. 60, 3091–3097 (2009).

65 Izmirly P.M, Llanos C, Lee LA, Askanase A, Kim MY, Buyon JP. Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum. 62, 1153–1157 (2010).

66 Willis R, Seif A, McGwin G et al. Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus 21(8), 830–835 (2012).

67 Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta M. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 69, 20–28 (2010).

68 Østensen M, Förger F. Management of RA medications in pregnant patients. Nat. Rev. Rheumatol. 5, 382–390 (2009).

n� Comprehensive survey on immunosuppressive drugs and biological agents used for treatment of RA and systemic lupus erythematosus.

69 Izmirly PM, Kim MY, Llanos C. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-

associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann. Rheum. Dis. 69(10), 1827–1830 (2010).

70 Motta M, Tincani A, Faden D et al. Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. J. Perinatol. 25, 86–89 (2005).

71 Park-Wyllie L, Mazzotta P, Pastuszak A et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62, 385–392 (2000).

72 Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod. Toxicol. 18(1), 93–101 (2004).

73 Cowchock FS, Reece EA, Balaban D et al. Repeated fetal losses associated with antiphospholipid antibodies; a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol. 166, 1318–1323 (1992).

74 Goldstein LH, Dolinsky G, Greenberg R et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res. A Clin. Mol. Teratol. 79, 696–701 (2007).

75 Akbari M, Shah S, Velayos FS, Mahadevan U, Cheifetz AS. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflamm. Bowel Dis. 19(1), 15–22 (2013).

n� Systematic review and meta-analysis to evaluate the fetal effects of thiopurine exposure during pregnancy or at the time of conception in women and men with inflammatory bowel disease.

76 Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed hemopoiesis in the babies of renal allograft patients. Br. J. Obstet. Gynecol. 92, 233–239 (1985).

77 Hoeltzenbein M, Elefant E, Vial T et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am. J. Med. Genet. (Part A) 158A(3), 588–596 (2012).

78 Østensen M, Förger F. Treatment with biologics of pregnant patients with rheumatic diseases. Curr. Opin. Rheumatol. 23, 293–298 (2011).

79 Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations

after first-trimester exposure to ACE inhibitors. N. Engl. J. Med. 354, 2443–2451 (2006).

80 Les I, Ruiz-Irastorza G, Khamashta MA. Intensity and duration of anticoagulation therapy in antiphospholipid syndrome. Semin. Thromb. Hemost. 38(4), 339–347 (2012).

81 Danza A, Ruiz-Irastorza G, Khamashta MA. Antiphospholipid syndrome in obstetrics. Best Pract. Res. Clin. Obstet. Gynecol. 26(1), 65–76 (2012).

82 Cooper BP, Scharff DP, Elliott M, Rotter B. The impact of SLHS program on perinatal indicators. Matern. Child Health J. doi:10.1007/s10995-012-1101-0 (2012) (Epub ahead of print).

83 Carmichael SL, Yang W, Feldkamp ML et al. National birth defects prevention study. Reduced risks of neural tube defects and orofacial clefts with higher diet quality. Arch. Pediatr. Adolesc. Med. 166(2), 121–126 (2012).

84 Chandler AL, Hobbs CA, Mosley BS et al. National birth defects prevention study. Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity. Birth Defects Res. A Clin. Mol. Teratol. doi:10.1002/bdra.23068 (2012) (Epub ahead of print).

85 Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide MV, Aguirre C. Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage. Arthritis Care Res. 62(8), 1160–1165 (2010).

86 Ritterhouse LL, Crowe SR, Niewold TB et al. Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 70, 1569–1574 (2011).

87 Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. PARIS Collaborative Group. Antiplatelet agents for prevention of preeclampsia: a meta-analysis of individual patient data. Lancet 369(9575), 1791–1798 (2007).

88 Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van der Post JA, von Dadelszen P, Mol BW, Pajkrt E; EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of preeclampsia: a systematic review and meta-analysis. BJOG 119(7), 778–787 (2012).

counseling women with systemic lupus … (possible for all patients including those positive for apl...

Documents