Introduction

Lupus is a disease that is at least ten times more common in women than in men. It most frequently presents during the reproductive years but can develop at any age from 18 months to 90 years. There has been concern that oestrogen can exacerbate the disease following studies done in mice and humans. In the past, there was considerable concern that lupus would flare during pregnancy with adverse effects for both the mother and baby. Until about ten years ago women were often counselled to avoid pregnancy if they suffered from systemic lupus. It is now realised that this advice should be modified depending on the type of disease that the woman has and the type of drugs that she requires to control it. Preventing pregnancy with contraception is also an important area for consideration. Women who enter the menopause often wish to consider hormone replacement therapy. These issues will be discussed in this chapter as well.

Pregnancy and Lupus

When should a woman with lupus become pregnant?
The best time for a woman with lupus to become pregnant is when her disease has been inactive for at least 6 months and she has been on stable therapy with low dose prednisolone (10mg or less/daily), hydroxychloroquine and/or azathioprine if needed. It is particularly important that renal and neurological disease are stable before a woman becomes pregnant as these conditions can have very serious consequences if they deteriorate during pregnancy. It is also important to consider other drugs that the woman may be taking and to ensure that these are also appropriate for pregnancy before the woman becomes pregnant. For example, ACE inhibitors should preferably be stopped before pregnancy or at the latest when pregnancy is confirmed by positive pregnancy test. Similarly, warfarin needs to be changed to oral aspirin and subcutaneous heparin when the woman becomes pregnant. However, it is not practical to maintain a woman on subcutaneous heparin for many months whilst she tries to become pregnant, as well as during pregnancy. Proton pump inhibitors (lansoprazole or omeprazole specifically) or ranitidine may be used in pregnancy to reduce acid reflux and indigestion as there is increasing data showing no concerns in pregnancy.

What is the risk of lupus flare during pregnancy?
Studies have shown variable results with some showing an increased rate of lupus flare during pregnancy and others showing no increase in the rate of flare compared to the non-pregnant state. Even the studies that have shown an increase in flare rate during pregnancy have found that these are usually mild or moderate flares involving the skin and joints predominantly, rather than renal disease, providing that the woman is stable before pregnancy. Patients with inactive lupus prior to pregnancy have the least risk of developing lupus flare during pregnancy.

Renal disease can deteriorate during pregnancy, particularly if it has been active at the start of pregnancy and can be confused with pre-eclampsia with which it can also co-exist. It is very important during pregnancy to identify whether changes in clinical state are due to active lupus disease, physiological or pathological changes associated with pregnancy, or some other co-morbid condition. Patients should be regularly reviewed by their physician as well as by their obstetrician. Some pregnant patients develop bland effusions of the knees during pregnancy, carpal tunnel syndrome, proteinuria with hypertension and ankle swellings due to pre-eclampsia, or non-specific arthralgia and myalgia without having evidence of a lupus flare. To diagnose a lupus flare there must be an overt lupus rash (photosensitive or not), inflammatory synovitis affecting the joints with tenderness and/or swelling, hair loss or mucosal ulceration. To diagnose lupus nephritis during pregnancy there should be cells and/or casts in the urine and usually a marked increase in proteinuria before a rise in blood pressure. In preeclampsia blood pressure usually rises before the onset of proteinuria.

Greater confidence that lupus is the cause of a flare including increased proteinuria is obtained if there is a simultaneous rise in anti-double stranded DNA antibodies and a fall in complement C3 and C4 protein. Complement protein C3 and C4 normally rise during pregnancy so even remaining low in the normal range can be considered abnormal in the later phase of pregnancy and any fall at all of 25% or more should be considered an indicator of active disease during pregnancy. The measurement of ESR is not reliable in pregnancy as it rises nonspecifically in all patients.

Treatment of lupus flare in pregnancy
Lupus patients whose disease becomes more active in pregnancy can have an increase in their prednisolone dose or start low dose prednisolone for the first time. Prednisolone is largely inactivated by an enzyme in the placenta and very little reaches the baby. However, prednisolone, particularly at doses above 10mg per day can be associated with an increased risk of hypertension, pre eclampsia, diabetes mellitus, infection, osteoporosis and premature delivery. Azathioprine and hydroxychloroquine do not appear to harm the baby from a number of studies, although very few controlled trials. Evidence suggests that the outcome for mother and baby is much better if the mother’s disease is prevented from flaring by continuing these drugs or starting them if the disease flares during pregnancy, rather than by stopping the drugs which used to be the practice in the past. In contrast, drugs such as methotrexate, mycophenolate mofetil and cyclophosphamide must be discontinued preferably 3 months before pregnancy because they are teratogenic and they should not be started during pregnancy. Azathioprine is usually used instead of these drugs while trying to conceive and in pregnancy or breast-feeding. Ciclosporin or tacrolimus may be used with careful monitoring for high blood pressure, renal impairment and diabetes mellitus. Rituximab should be stopped 6 months before pregnancy as it has a long half-life and can cross the placenta from 16 weeks gestation. However, belimumab, which has a shorter half-life, may be continued until pregnancy is confirmed. If the patient has been exposed to leflunomide there are specific procedures that need to be undertaken to wash out the drug.

Other complications that can affect the mother with SLE in pregnancy
1) The most important complication of lupus disease that can affect the mother is thrombosis. All women with lupus are at increased risk of thrombosis, particularly those with anti-phospholipid antibodies (usually measured as anti-cardiolipin antibodies or lupus anticoagulant on two occasions at least 6 - 12 weeks apart). Anti-phospholipid antibody syndrome is characterised by recurrent venous or arterial thrombosis and recurrent miscarriages or other adverse obstetric history such as premature delivery, pre-eclampsia or still birth. Patients with a history of anti phospholipid antibody syndrome are likely to require subcutaneous heparin and oral aspirin throughout pregnancy. Patients with recurrent miscarriages alone, particularly if the first trimester, may be treated with just aspirin. Some units may also use aspirin to prevent thrombosis and pre-eclampsia in patients without antiphospholipid antibodies.

2) SLE patients on steroids and subcutaneous heparin during pregnancy are at increased risk of osteoporotic fractures and are often treated with calcium and vitamin D3 during pregnancy, although there is no evidence that this will reduce the risk of fractures. Fortunately, the fracture risk is small, except for women who are on very high dose steroids and/or have had many courses of subcutaneous heparin.

3) There is also an increased risk of diabetes mellitus in patients who have been given steroids, especially those on 10mg prednisolone/day or more during pregnancy. Many units will arrange a glucose tolerance test during the second trimester of pregnancy to look for evidence of impaired glucose tolerance.

Foetal outcome in lupus pregnancy

1) There is an increased risk of miscarriage and still birth in patients with lupus. The risk is greatest in those with a history of previous foetal loss due to either miscarriage or still birth, particularly in those with anti phospholipid antibodies or active disease during pregnancy. In the past there was some data suggesting that patients with a history of renal disease were more at risk from foetal loss, but more recent studies have not confirmed this observation, probably due to changes in treatment during pregnancy.

2) Premature delivery is more common in women with lupus. This is a delivery under 38 weeks of gestation. The delivery is sometimes spontaneous, but more often induced due to concerns about poor foetal growth. Impaired foetal growth (restricted intrauterine growth) may herald the risk of miscarriage or still birth. Once the baby is mature enough to be delivered and maintained on a neonatal special care baby unit, it may be advisable to consider induction of pregnancy or even emergency caesarean section in order to deliver the baby before it dies in utero. Premature delivery is also sometimes required to protect the mothers health in case of pre eclampsia, particularly if it is progressing to eclampsia or if she has very severe lupus disease requiring treatment with cytotoxic agents such as cyclophosphamide. If intrauterine growth restriction is detected during the pregnancy and the mother is known to have lupus anticoagulant and/or anti cardiolipin antibodies a case may be made to start subcutaneous heparin but intervention during pregnancy has not yet been studied to determine whether or not this will improve the outcome. All the existing studies to date are on the prevention of miscarriage and still birth by treating patients from early in pregnancy based on their medical history.

3) Congenital abnormalities Major abnormalities occur no more frequently in the babies born to mothers with lupus than other women, providing that the woman is only taking approved drugs such as prednisolone, hydroxychloroquine and azathioprine for her lupus. There is a documented increase in the rate of major congenital abnormalities in patients treated with cyclophosphamide, methotrexate and mycophenolate mofetil.

The commonest congenital abnormality that can be related to SLE is congenital heart block. This occurs in approximately 1% of lupus patients with anti-Ro or antiLa antibodies and is due to transmission of anti-Ro and/or anti-La antibodies between 16 and 28 weeks of pregnancy. Transmission of these antibodies cannot occur before 16 weeks. Transmission may occur later but the development of congenital heart block is usually detected by week 28, although it can occasionally be observed to start later than this and even after birth. Women who are known to have anti-Ro or anti-La antibodies should have foetal heart rate screening from week 16 onwards by their midwife or hospital unit. A few babies will die in utero due to congenital heart block and related cardiac complications. The majority that are born do well. However, about 30% will require a pacemaker during the first month of life, another 30% will require a pacemaker during the first year of life and a further approximately 30% will require a pacemaker by the age of 10 to 12 years old.

Children have no other evidence of disease due to the transplacental passage of antibodies apart from the occasional presence of a neonatal lupus rash and, very rarely, low platelets or thrombosis. Neonatal lupus rash does sometimes occur in babies born to mothers with anti-Ro and/or anti-La antibodies after delivery when they have been exposed to sunlight or UV light (for example for the treatment of jaundice). If a mother has had a previous baby with congenital heart block, the risk of a subsequent baby having this complication is about 20%. If a mother has a baby who previously had neonatal lupus rash, the risk of neonatal lupus rash in the subsequent pregnancy is about 10% and the risk of congenital heart block is about 20%. Low platelets are rare but most common in babies born to mothers with antiphospholipid antibodies or a history of immune mediated thrombocytopenia.

Contraception

Although recent studies have shown no increased risk of serious flare in patients with lupus being treated with oestrogen containing contraceptives, it is still advisable to be cautious about the use of these agents in women with SLE. It should be particularly noted that they may increase the risk of thrombosis and women with a history of anti phospholipid antibody syndrome should not be given oestrogen containing contraceptive unless they are very reliably anticoagulated with warfarin and have stable INR. They should be aware that oestrogen will increase their risk of a further thrombosis. In general, women that have the lupus anticoagulant or anti-phospholipid or anti-cardiolipin antibodies should not be given oral contraceptives containing oestrogen.

Women with lupus usually do well with progesterone-only contraception. Most women prefer the intra-muscular injections of Depoprovera to the oral progesterone-only pills that have to be taken very reliably within 2 hours of the same time each day, and even the longer lasting progesterone-only pills as both types of pill are often associated with intra-menstrual bleeding. Barrier methods are to be encouraged particularly in young women not in a stable relationship as it will help reduce the risk of the transmission of infection. The progesterone containing coil, such as the Mirena coil is often well tolerated by women with lupus and in a stable relationship as associated with no increased risk of infection. Intra-muscular progesterone injections, such as Depo Provera, and the progesterone containing coil can be used in women with anti phospholipid antibody syndrome including those on warfarin. They should be advised that there is some risk of bleeding when the progesterone injections are given and in the first few months after the progesterone containing coil is inserted, but that menstrual periods normally become lighter thereafter.

Hormone Replacement Therapy

Women with SLE are at increased risk of premature cardiovascular disease. They are also at risk of osteoporotic fractures, particularly if they have been treated with steroids. In the past, it was hoped that hormone replacement therapy would help to reduce the risk of both of these complications. Unfortunately, recent studies have shown an association between hormone replacement therapy and increased cardiovascular risk. As a result, these drugs should be used with great caution in women with systemic lupus erythematosus, since the risk of premature cardiovascular disease is at least as great as that of diabetics if not higher. Some patients will opt to have hormone replacement therapy for control of menopausal symptoms despite the risks of premature cardiovascular disease and the other known side effects of hormone replacement therapy (including malignancy and thrombosis). These women should only be given HRT after trials of other methods of symptom control and extensive discussion about the risks that they are undertaking. The situation should then be reviewed regularly as longer duration of exposure to HRT is associated with increasing risk of cardiovascular disease.

Conclusion

Women with lupus can often have successful pregnancies. It is very important that they receive pre-pregnancy counselling to ensure that they are aware of the risks of pregnancy and so that their drug therapy can be rationalised before they become pregnant. Those on anticoagulation with warfarin need detailed instructions about how to switch to subcutaneous heparin when they become pregnant. Planning pregnancy to be at a time when the woman has had inactive disease for 6 months or more, and is on an appropriate drug therapy, will be facilitated by discussions about contraception. In general, progesterone-only injections and the Mirena coil are most suitable for women who do not find barrier methods reliable enough. Sometimes both methods should be used. Once the woman goes into the menopause the use of hormone replacement therapy should be considered very cautiously, particularly in women with antiphospholipid antibody syndrome who are more prone to thrombosis. The risk of premature cardiovascular disease is not well recognised in lupus patients but should be as it is at least as great as the risk in diabetics and, in most cases, hormone replacement therapy is not advisable.

Prof Caroline Gordon
Emeritus Professor of Rheumatology
Rheumatology Research Group
Institute of Inflammation and Ageing
University of Birmingham

Honorary Consultant Rheumatologist
City Hospital
Sandwell and West Birmingham Hospitals NHS Trust