Managing pregnancy in inflammatory rheumatological diseases

Historically, pregnancy in women with many inflammatory rheumatic diseases was not considered safe and was discouraged. Combined care allows these pregnancies to be managed optimally, with the majority of outcomes being favorable. Disease activity at the time of conception and anti-phospholipid antibodies are responsible for most complications. Disease flares, pre-eclampsia, and thrombosis are the main maternal complications, whereas fetal loss and intrauterine growth restriction are the main fetal complications. Antirheumatic drugs used during pregnancy and lactation to control disease activity are corticosteroids, hydroxychloroquine, sulphasalzine, and azathioprine. Vaginal delivery is possible in most circumstances, with cesarean section being reserved for complications.


Fertility
Infl ammatory rheumatological diseases aff ect women of childbearing age, and fertility is an important consideration. Fertility is not usually aff ected by the rheumatic diseases; however, factors that impact on female fertility include cytotoxic drugs, amenorrhoea accompanying severe fl ares, and renal insuffi ciency [3].
Th e main cytotoxic drug that poses a threat to fertility is cyclophosphamide. It is known to cause premature ovarian failure, and the risk is dependent on the age at which it is started, the duration of treatment, and the cumulative dose. Boumpas and colleagues [4] showed that none of the women who were under the age of 25 years and who had not more than 7 pulses of intravenous cyclophosphamide developed sustained amenorrhoea. However, all the women who were over 30 years and who received at least 15 intravenous pulses of cyclophos pha mide developed sustained amenorhoea [4]. Th e risk varies with the regime used, and another study of 84 patients with SLE showed that two thirds of cases had successful pregnancies [5,6].
Elizur and colleagues [7] suggested that fertility preservation should be off ered to all women with severe renal/ extrarenal manifestations of SLE or other systemic rheumatic diseases requiring cyclophosphamide at doses that might preclude them from having their own biological child. Options available include ovulation induc tion therapy, oocyte or embryo cryopreservation, or in vivo maturation of oocytes. Ovulation induction therapy may promote fl ares in patients with lupus and precipitate thromboembolism in women with antiphospholipid antibodies [8].
Eff ects of the rheumatological disease and pregnancy on the mother Systemic lupus erythematosus

Disease activity
Th ere is much debate in the literature as to whether lupus activity increases during pregnancy. Studies have involved varied cohorts of patients and controls, making the studies diffi cult to compare. Th e hormonal changes that occur in pregnancy seem to be responsible for inducing lupus activity, and it appears that 40% to 50% of patients have a measurable increase in disease activity. Th e risk of a severe fl are is lower and is estimated at 15% to 30%. Flares are typically cutaneous, arthritic, or hemato logical. Th e risk of fl are is increased if there is evidence of a fl are within 6 months prior to conception, active lupus nephritis, very active lupus in the past, and/ or discontinu a tion of medication [9][10][11]. Th ere is a risk of fl ares in the postpartum period even if disease has been in remission before and during pregnancy. Diagnosis of lupus fl are is important to distinguish from pregnancyrelated physio logical changes or complications. Th ese features are outlined in Table 1 [12].

Pregnancy eff ects
Women with SLE are at an increased risk of developing medical complications during pregnancy, regardless of whether their lupus is active or not [13]. Owing to hormonal changes, the risk of thrombosis is increased two to three times during pregnancy and the fi rst 6 weeks after delivery. Th ere is a 5% to 10% risk that a pregnant woman with SLE will develop a thrombosis during this period, even in the absence of APS [14].
Women with SLE are at higher risk of maternal complications (disease fl ares, pregnancy-induced hypertension [PIH], pre-eclampsia, eclampsia, diabetes, or thrombosis) and fetal complications (recurrent fetal loss, growth restriction, or fetal distress in labor) [13]. As a result, they tend to have longer hospital stays and a higher rate of cesarean section. Maternal mortality, though rare, is increased approximately 20 times compared with that of women in general in the US [13,15].
Pre-eclampsia is defi ned as PIH in association with proteinuria (greater than 0.3 g in 24 hours) and edema, but virtually any organ may be aff ected. Th is is a common pregnancy-related complication in SLE. About 25% of women with SLE develop pre-eclampsia, and the risk is higher for women with pre-existing hypertension, a history of lupus nephritis, or anti-phospholipid antibodies [13,15]. Diff erentiating between active lupus nephritis and pre-eclampsia is crucial, and it is important to note that the two can coexist. Th e presence of hypertension with recent-onset proteinuria makes preeclampsia more likely than lupus nephritis, as hypertension is very rarely an early sign of active renal disease. Red or white cells in the urine in the presence of proteinuria are more likely to be due to lupus nephritis (after excluding infection, bleeding, or calculi). Urinary casts are the best marker for active renal lupus. Blood tests that help to distinguish active renal disease from pre-eclampsia include an increase in anti-doublestranded DNA (anti-dsDNA) titres or a 25% decrease in complement levels (C3 and C4) (even within the normal range) or both [12].

Antiphospholipid syndrome 1. Disease activity
APS is characterized by the presence of anti-phospholipid antibodies and either vascular thrombosis or pregnancy morbidity [16]. Primary APS occurs in isolation in 50% of patients, whereas secondary APS can be associated with any other autoimmune disease, most commonly SLE. Th e increased risk of thrombosis during all pregnancies is increased further in patients with APS and most often presents as deep vein thrombosis, pulmonary emboli, stroke, hepatic infarction, recurrent miscarriages, and premature delivery for fetal distress or pre-eclampsia. Anti-phospholipid antibodies may also initiate an infl ammatory process involving the activation of complement that aff ects placental function and results in poor pregnancy outcomes [17]. Patients with lupus anticoagulant and/or previous pulmonary emboli are at risk of pulmonary hypertension that may deteriorate in pregnancy which is associated with a 50% risk of maternal mortality [18,19].

Pregnancy eff ects
Th e presence of anti-phospholipid antibodies predisposes the patient to PIH, pre-eclampsia, and eclampsia, the last of which usually presents as one or more convulsions superimposed on pre-eclampsia. Pre-eclampsia may occur in patients with APS pregnancy earlier than in healthy women, from 22 weeks [20]. HELLP syndrome is a thrombotic micro angiopathic disorder consisting of hemolysis, elevated liver enzymes, and low platelets. It presents typically in the third trimester but in patients with APS may present with pre-eclampsia earlier than in healthy women, even as early at 15 weeks of gestation [21][22][23][24].

Rheumatoid arthritis and other infl ammatory arthropathies/spondyloarthropathies 1. Disease activity
In RA, provided that disease activity is stable at the time of conception, approximately 75% of patients notice an improvement in their condition within the fi rst trimester and approximately a quarter go into remission [25]. Th e risk of fl ares is increased in the postpartum period, and the majority of women have fl ares within the fi rst 3 months after delivery but only about 40% are of moderate severity [25,26]. Th e immunological basis for these changes remains uncertain but is thought to involve changes in regulatory T cells, monocytes, and galacto sylation levels of immunoglobulin G [27][28][29][30][31].
Pregnancy generally improves physical functioning in patients with RA but not in those with ankylosing spondylitis. Emotional and mental health during pregnancy are unaff ected in both conditions [32]. Women with spondyloarthropathy generally notice an improvement in their peripheral arthritis and uveitis during pregnancy [33]; however, spinal disease tends to remain unchanged or worsen. Postpartum fl ares are common in the fi rst 3 months following delivery and are unrelated to disease activity during pregnancy, duration of lactation, or time of return of menses [14].

Pregnancy eff ects
Pregnancy outcomes for women with RA and spondy loarthropathies tend to be favorable; however, these women have increased lengths of hospital stay, increased rate of premature rupture of membranes, and higher cesarean section delivery rates in comparison with healthy women [15]. Th ere is no increased risk of pre-eclampsia in RA [34].

Systemic sclerosis 1. Disease eff ects
Scleroderma, the skin changes of SSc, tends not to change in pregnancy. Raynaud phenomenon usually improves because of the physiological increase in cardiac output. Gastroesophageal refl ux disease is seen to worsen but is a common presentation in all pregnant women. Recurrent vomiting can cause Mallory-Weiss tears in the esophagus already thinned by disease-related fi brosis; therefore, prompt management is of importance in the prevention of life-threatening bleeding [35]. One of the most serious complications that occurs in pregnant women with SSc is renal crisis due to acute-onset severe hypertension. A daily increase in serum creatinine and lack of proteinuria in the early stages support a diagnosis of renal crisis due to SSc. Renal crisis is most common in patients with early diff use SSc (within 5 years of symptom onset), anti-tropoisomerase and anti-RNA polymerase III antibodies, and exposure to high-dose corticosteroids [35]. Pulmonary hypertension is another serious complication and is associated with 50% maternal mortality, and most vigilance is required 48 to 72 hours after delivery. Screening should be done before pregnancy, and termination should be off ered if the complication is diagnosed in pregnancy [36].

Pregnancy eff ects
Women with SSc have a higher rate of hypertensive disease, including pre-eclampsia, and have an increased length of hospital stay compared with normal women [15]. Elevated liver function tests and proteinuria with edema are more common in pre-eclampsia and HELLP syndrome than in SSc renal crisis. Hypertension or renal dysfunction due to pre-eclampsia, but not due to active SSc, will be resolved by delivery [12].

Disease eff ects
Th ere are very few prospective studies of vasculitides in pregnancy. Vasculitides can occur at any age but are generally more frequent in men and in women beyond their reproductive period [37]. Planning conception at a time of disease inactivity usually allows women with Wegener granulomatosis (WG), polyarteritis nodosa (PAN), or Churg-Strauss syndrome to remain well during pregnancy. Th ey are at risk of deteri or ation during pregnancy and the fi rst 6 weeks after delivery should conception occur when the disease is inadequately treated or newly active [38,39].
Only 38 cases of WG have been reported in the literature: 21 were in remission at conception, 13 were diagnosed during pregnancy, and 4 had active disease at the time of conception. Flares have a bimodal distri bution, most commonly occurring either in the fi rst or second trimester or in the month after delivery. Maternal death has been reported twice, once following thera peutic abortion and once 1 month after delivery [38,40,41].
Th ere are eight reports of pregnancy and PAN [12,39,42]. Conceiving at a time when PAN is active puts the mother at higher risk of death; hence, therapeutic abortion is recommended in the early phase of pregnancy, or high-dose corticosteroids with cyclophos phamide are recommended in the late stages [39].
In Churg-Strauss syndrome, respiratory and cardiac systems are most commonly aff ected during relapse. Asthma is more common but cardiac involvement can lead to irreversible myocardial damage requiring heart transplantation, so careful pre-pregnancy screening and management of pregnancy are critical [39,43].
In Takayasu arteritis (TA), severe aortic valvular disease and aortic aneurysm are risk factors for maternal morbidity and fatality; therefore, pregnancy is discouraged in these patients [39]. Less frequently, heart failure, renal insuffi ciency, and cerebral hemorrhage have been reported. Despite these complications, the outcome of pregnancy is generally favorable provided that there is little delay in seeking medical advice [44].
Behçet disease (BD) improves during pregnancy in most patients; however, exacerbations occurred in about a sixth of patients in a case control study [45]. BD is associated with an increased risk of thrombosis and vascular involvement, including central venous thrombosis [46].

Pregnancy eff ects
Hypertensive disease is more common in women with WG and renal involvement than in normal pregnant women. It is the presenting feature in TA and pregnancy, and pre-eclampsia complicated 62% of cases in a recent single-center Indian study [47]. Pregnancy complications and cesarean section were signifi cantly higher in BD patients than in controls [45], as with most other vasculitides, particularly TA and WG. Like lupus nephritis, renal vasculitis needs to be distinguished from pre-eclampsia; however, blood tests (c-ANCA [antineutrophil cytoplas mic antibody and classical cyto plasmic staining complete heart block] and anti-PR3 [antiproteinase-3]) are helpful only in diagnosing renal vasculitis due to WG.

Fetal loss
'Fetal loss' incorporates spontaneous abortion from less than than 10 weeks, miscarriages from 10 to 19 weeks, and stillbirths from 20 weeks of gestation. Th e most important factors in predicting fetal loss in SLE, APS, SSc, and vasculitis are previous fetal loss, disease activity at conception (especially renal), maternal hypertension, and the presence of anti-phospholipid antibodies [12,48]. Fetal loss is not increased in those with infl ammatory arthropathies or spondylo arthro pathies in the absence of maternal complications.

Intrauterine growth restriction
Th e risk of intrauterine growth restriction (IUGR) in SLE and APS pregnancies is about three times that in controls [15]. Th e risk of IUGR is increased in those with active disease at conception and in those with anti-phospholipid antibodies [9,11,16]. IUGR increases the risk of pre mature delivery and is thought to occur due to uteroplacental dysfunction secondary to thrombosis and comple ment activation; however, the exact mechanisms are unknown [17].

Premature delivery
Premature delivery, which is defi ned as occurring before 38 weeks of gestation, is common in lupus, APS, SSc, and the vasculitides [12,13,35,44,49]. Pre-term delivery is not associated with RA [34]. Th e most important compli cation of premature delivery is respiratory distress syndrome. In this condition, the newborn can suff er from respiratory distress due to insuffi cient surfactant. If premature delivery is imminent, the mother should be given a course of corticosteroids to promote fetal lung development at least 24 hours before birth. Th e current UK guidelines recommend two doses of betamethesome 12 mg intramuscularly (12 hours apart) or four doses of dexamethasone 6 mg (12 hours apart) [50].

Neonatal lupus
Neonatal lupus is a model of passive autoimmunity in mothers who carry anti-Ro (SSA) or anti-La (SSB) antibodies or both. Antibodies cross the placenta from about week 16 and are associated with (a) irreversible con genital complete heart block (CHB) in the fetus or (b) transient photosensitive rash on the face or scalp or various liver and hematological abnormalities or neuro logical manifestations in the newborn or (c) both. CHB is defi ned as atrioventicular block diagnosed in utero, at birth, or within the neonatal period (0 to 27 days after birth) and is present in approximately 1% to 2% of women with anti-Ro/La antibodies [51][52][53]. CHB is permanent, and although most children do well with pacemakers, the cumulative probability of survival at 3 years of age was only 80% in one report [52]. Neonatal lupus rash is present in 10% to 20%, and laboratory abnormalities (anemia, thrombocytopenia, neutropenia, and abnormal liver function tests) were detected in up to 27% of babies in a prospective study [51]. Th e risk of recurrence of CHB is about 20% in a subsequent pregnancy after an aff ected child [53].
Women who are at risk of having a baby with CHB are recommended to have regular monitoring [54], but guide lines vary among countries and among units. In the UK, the midwife should listen to fetal heart rate on a weekly basis to identify bradycardia from week 16 onwards and the baby should have heart rate confi rmed while being scanned monthly. Formal fetal echocardiography occurs at the 20-week anomaly scan, and further echocardiograms are done if an abnormality is suspected. Partial heart block can be identifi ed on fetal electrocardiogram [54]. Intravenous immunoglobulin (IVIG) has been reported to successfully treat severe thrombocytopenia associated with neonatal lupus [55], but IVIG does not prevent recurrence of CHB [56]. All babies born to mothers with anti-Ro/La should have an electro cardiogram after birth to look for fi rst-and second-degree heart block as they may progress to third-degree later.

Neonatal autoimmune thrombocytopenia
Transmission of anti-platelet antibodies across the placenta in women with APS is recognized to cause thrombocytopenia in infants. Occasionally, this presents as intracranial hemorrhage [57]. Th rombocytopenia usually resolves within 6 months as the mother's antibodies are cleared from the circulation. IVIG may be used as treatment for severe thrombocytopenia [58].

Pre-pregnancy considerations
To avoid or reduce the complications discussed above, pre-pregnancy planning and screening must be carefully undertaken. Combined care involving rheumatologists, nephrologists, hematologists, or other relevant physicians, obstetricians, and anesthetists is preferred for all but simple infl ammatory arthropathies. Management of the pregnant patient with infl ammatory rheumato logical disease should be tailored to the individual's disease activity and history. Pregnancy during disease remission provides the best results as described above, and patients should be advised not to get pregnant until the disease has been well controlled for 6 months on non-teratogenic drugs that can be continued in pregnancy to reduce the risk of fl ares. A review of all medication that might aff ect pregnancy should be undertaken.
Side eff ects of teratogenic medication, such as methotrexate, cyclophosphamide, mycophenolate mofetil, or lefl unomide, must be discussed prior to commencing treatment, and information on contraceptive methods should be off ered with advice on when the drugs and contraception should be stopped prior to pregnancy ( Table 2). Most contraceptive choices, including emergency contraceptive choices, can be off ered to patients with rheumatological diseases, but there is a potential risk of thrombosis in APS if the patient is not fully anticoagulated. Estrogen-containing contraceptives can be used with care in patients with mild non-active lupus but, owing to the increased risk of thrombosis, should be avoided in women with anti-phospholipid antibodies or APS [59][60][61].
Disease activity should be assessed by standard criteria for each disease and potential risk factors for pregnancy complications -including anti-Ro/-La and anti-phospho lipid antibodies (including IgG and IgM anticardiolipin and β2 glycoprotein-I antibodies and lupus anticoagulant), hypertension, and diabetes and raised serum creatinine, 24-hour proteinuria, or protein/ creatinine ratio -should be identifi ed [12,48]. Echocardio graphy and lung function tests should be done if there have been cardiac, lung, or thrombotic complications, particularly if there is a risk of pulmonary hypertension [18,19,36].
As with other women planning pregnancy, a healthy diet and appropriate exercise are recommended and smoking, using illicit drugs, or drinking alcohol are discouraged. Folic acid (0.4 mg) should be started 3 months prior to pregnancy and continued until 12 weeks of gestation to prevent neural tube defects [62]. Women taking folate antagonists such as sulphasalazine are usually advised to take 5 mg daily throughout pregnancy and lactation.

Drugs
A summary of drugs available for use in patients with infl ammatory rheumatological conditions in pregnancy is provided in Table 2. Specifi c attention should be given to the most commonly used drugs: analgesia, corticosteroids, sulphasalazine, azathioprine, hydroxychloroquine, aspirin, and heparin and those that are contraindicated [49,[63][64][65][66].
Paracetamol is the fi rst-line analgesic. Mild opioids such as codeine or pethidine are preferred if needed, as they can be easily reversed. Th e concerns are that the newborn may present with respiratory depression or opioid dependency or both [67]. Tramadol has embryotoxic eff ects in animals and should be avoided.
Corticosteroids can be divided into non-fl uorinated steroids (prednisolone and methyprednisolone) and fl uorinated steroids (betamethasone and dexamethasone) [64]. Approximately 90% of prednisolone is metabolized by the enzyme 11-β-hydroxysteroid dehydrogenase in the placenta; as a result, about 10% reaches the fetus. It is widely used, therefore, to treat maternal disease or fl ares (or both) in pregnancy. Fluorinated steroids are not metabolized by the placenta and reach the fetus in their active form. Th ese steroids are used to treat or prevent fetal complications, but reversal of CHB has not been achieved [54,64,68]. All steroids increase the maternal risk of hypertension, pre-eclampsia, premature rupture of membranes, infection, and diabetes, so the lowest eff ective dose must be used (ideally not more than 15 mg/day).
Sulphasalazine has been used for many years for arthropathies and infl ammatory bowel disease in preg nancy. Hydroxychloroquine is an anti-malarial used mainly in the treatment of SLE and reduces the risk of maternal disease fl are and possibly thrombosis and does not cause fetal damage. Women are recommended to continue with hydroxychloroquine throughout preg nancy and lactation [14,69]. Azathioprine is a cytotoxic immunosuppressant used mainly in SLE and vasculitis. Th e fetus lacks the enzyme inosinatopyrophophorylase, which is required to convert azathioprine to its active metabolite 6-mercaptopurine, and therefore azathioprine is safe to use in pregnancy. Azathioprine can be used to control severe maternal disease, and doses of not more than 2 mg/ kg per day are associated with few side eff ects [64].

Treatment and prevention of fl ares
Provided that conception occurs during remission, the risk of fl ares is low. Th e patient's condition should be kept stable on medication that can be continued throughout pregnancy, such as prednisolone, hydroxychloroquine, sulphasalazine, and azathioprine. If these drugs are stopped, there is an increased risk of fl are [14,69,70].
Mild fl ares of lupus, vasculitis, or arthritis are usually treated with low-dose prednisolone (less than 15 mg per day). Higher doses or intravenous pulse methylprednisolone is used for severe fl ares. Non-teratogenic medication such as azathioprine, ciclosporin, or tacrolimus may be used. Cyclophosphamide and mycophenolate mofetil are occasionally used when all other options have been exhausted in the third trimester [11,38,39].

Management of recurrent pregnancy losses
Managing recurrent fetal losses depends on under standing the mechanism(s) underlying fetal loss. Th ree specifi c causes have been identifi ed: disease activity (which is controlled as discussed above), maternal com pli cations such as pre-eclampsia, or thrombosis. Th rombosis is most commonly associated with anti-phospholipid antibodies, and treatment occurs in one of two ways. Th e fi rst is the use of antiplatelet/anticoagulant therapy, mainly aspirin and heparin. In the literature, there is much debate about the correct regime, and optimal doses have not been agreed upon. Th e current recommended guideline for women who have recurrent miscarriages is combination therapy of low-dose aspirin with lowmolecular-weight heparin [64,71,72]. A randomized, controlled trial found no diff erence between giving aspirin only versus giving aspirin and heparin [73]. However, in that trial (as in a number of studies), not all patients had confi rmed APS according to the Sydney criteria, making results diffi cult to interpret [16].

Treatment and prevention of hypertension{
Non-teratogenic anti-hypertensives should be taken before and during pregnancy. Labetalol, nifedipine, methyl dopa, and hydralazine are used to control hypertension. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated because of teratogenicity. Th ey are the mainstay of treatment in renal crisis of SSc and may be used after appropriate discussion with the mother if hypertension is lifethreatening [36]. Aspirin may reduce pre-eclampsia and prematurity. Many centers use it in high-risk pregnancies, including lupus and other systemic autoimmune diseases, to reduce the risk of pre-eclampsia and thrombosis [74,75]. If pre-eclampsia is severe or progresses to eclampsia, delivery is the defi nitive treatment.

Treatment of esophageal refl ux and dyspepsia
Dyspepsia is a common symptom in pregnant women and can be worsened by aspirin, non-steroidal antiinfl ammatory drugs, and corticosteroids. Antacids such as gaviscon are rarely suffi cient. Ranitidine, a histamine-2-antagonist, is used at doses of between 150 and 600 mg daily, especially in patients with SSc [76,77]. Th ere is less experience with proton pump inhibitors such as omeprazople, but they are probably safe in pregnancy [76,78].

Delivery
Women with chronic disease generally want to have a 'natural' delivery like healthy women. With eff ective prepregnancy planning and joint care, vaginal delivery should be possible; cesarean delivery is reserved for obstetric emergencies, those with a history of cesarean section who do not want a trial of vaginal delivery, and women with severe hip disease. However, to reduce the risk of stillbirth in patients with APS or active disease, induction may be advisable at 38 to 39 weeks. Detailed plans for delivery should be made by a multi-disciplinary team that includes the obstetrician, anesthetist, and relevant physicians at 36 weeks of gestation or earlier in patients with complications. Owing to the risk of placental insuffi ciency in SLE, APS, SSc, and vasculitis, babies need to be monitored by growth scans every 4 weeks throughout pregnancy and closely monitored during delivery for any signs of fetal distress. Disease-specifi c considerations for anesthesia are listed in Table 3. Epidural can be off ered for routine vaginal deliveries. For cesarean section, neuroaxial anesthetic can be performed; general anesthetic is reserved for obstetric emergencies (for example, placental abruption, uterine rupture, prolapsed umbilical cord, or fetal distress). Th e last dose of heparin should be given 12 hours before the epidural will be administered, and the fi rst dose after delivery should be 12 hours later. Aspirin may be given up until the time of delivery and is compatible with spinal and epidural anesthesia, although practice still varies among centers [79].

Breastfeeding
Breastfeeding has multiple health benefi ts for both the mother and child (Table 4) [80]. Table 5 summarizes  recommendations for treatment during lactation [49,[63][64][65][66]. It is widely agreed that prednisolone, sulphasala zine, and hydroxychloroquine are acceptable [64,69,81]. Azathioprine use during lactation remains more controversial [64,81] but has been used by us and others without obvious harm to the infant, as levels of the active metabolites are rare in breast milk and undetectable in the baby [64,82,83].

Conclusions
With careful planning, most women with infl ammatory rheumatological diseases can have successful pregnan cies (Table 6). It is important that conception occur when the disease has been inactive for at least 6 months and while the mother is taking non-teratogenic drugs. Th e mother and fetus require regular monitoring throughout pregnancy so that any complications can be detected Azathioprine and its metabolites detected in breast milk May be used at not more than 2 mg/kg per day after in low amounts, but abnormalities rare discussion with mother weighing up risk-benefi t Cyclosporin Wide variability in drug disposition May be used after discussion with mother weighing up risk-benefi t, preferably at doses lower than 2.5 mg/kg per day Cyclophosphamide Excreted in breast milk Contraindicated

Mycophenolate mofetil
No human studies Contraindicated due to theoretical risk Tumor necrosis factor-alpha Etanercept excreted in breast milk Not enough data, therefore should be avoided antagonists (for example, Infl iximab undetectable infl iximab, etanercept, and No studies with adalimumab adalimumab)

Anakinra
Unknown whether excreted in breast milk Not enough data, therefore should be avoided Abatacept Not known whether excreted in breast milk or whether Contraindicated due to theoretical risk absorbed systematically after ingestion

Rituximab
Unknown whether excreted in breast milk Not enough data, therefore should be avoided

Intravenous immunoglobulin
No published data May be used during breastfeeding after discussion weighing up risk-benefi t Heparin and low-molecular-Not excreted in breast milk Can be continued during breastfeeding weight heparin

Warfarin
Minimal excretion in breast milk Can be used while breastfeeding NSAID, non-steroidal anti-infl ammatory drug.
early and managed appropriately. Combined care involving obstetricians, rheumatologists, other relevant physicians, and anesthetists will promote the best outcomes for mother and baby.

Table 6. Key points in the management of patients with rheumatological diseases in pregnancy
With thorough pre-pregnancy planning, most pregnancies in women with infl ammatory rheumatic diseases are low-risk and have a favorable outcome.
Fertility is generally not aff ected by autoimmune rheumatic disease.
Systemic lupus erythematosus is the most widely studied rheumatic disease in pregnancy, and it is important to diff erentiate active lupus disease from pathophysiological changes of pregnancy.
Antiphospholipid syndrome is secondary to another autoimmune disease in 50% of cases. Anti-phospholipid antibodies are associated with an increased risk of thrombosis, fetal loss, pre-eclampsia, intrauterine growth restriction, and premature labor.
Rheumatoid arthritis and Behçet disease usually improve during pregnancy but are still associated with a risk of fl are in the postpartum period.
Disease at the time of conception is the most important factor in determining maternal and fetal outcome.
HELLP (hemolysis, elevated liver enzymes, and low platelets) and pre-eclampsia occur in women with autoimmune rheumatic disease (especially, antiphospholipid syndrome) earlier than in healthy women and must be distinguished from disease activity and treated appropriately.
Neonatal lupus is specifi c to mother with anti-Ro/La antibodies and can lead to irreversible congenital complete heart block, requiring a permanent pacemaker in aff ected children.
Drug therapy must be reviewed prior to conception and during pregnancy and breastfeeding in order to rule out any potential harmful side eff ects to the fetus/child.
Vaginal delivery is generally deemed safe. Cesarean sections are reserved for patients with obstetric complications.