The Importance of Planning Pregnancy in SLE
Many patients with SLE are young women in the reproductive age group. Some are young men who are also likely to want to have children. Most patients with SLE of either sex should be able to have children but it is wise to plan when to do so with the physician responsible for looking after the lupus disease. Furthermore it may be best to get additional advice from an obstetrician experienced in looking after women with SLE in pregnancy. The reasons for this advice are the subject of this article and should help patients discuss the relevant issues with their doctors. It should be remembered that only general principles can be covered in this article and that for any individual person, reading this should not replace getting specific advice from the relevant doctors caring for that person.
Fertility
The first issue to consider is fertility: can the person with SLE become pregnant? The vast majority of lupus patients have no problems with fertility. However, occasionally female lupus patients develop antibodies to ovarian tissue that interferes with the development of the egg during each monthly cycle and although they may still be having menstrual periods, they are not able to become pregnant. Sometimes they have a disrupted cycle or no periods at all. When this occurs, the cause should be looked into as there are several possible reasons. Anti-ovarian antibodies are a manifestation of a similar autoimmune process to the underlying cause of the main lupus disease.
The other cause of infertility linked to lupus is that due to the effects of the drug cyclophosphamide. Cyclophosphamide is an important and very useful drug for the treatment of severe lupus, particularly kidney and nervous system disease. Although it can cause infertility by damaging the cells that give rise to eggs (or sperm), this process is not usually a significant problem in women aged 30 or under who are given short courses (for example about 6 months). However, with increasing age (especially over the age of 34) and longer courses of treatment with cyclophosphamide the risks are higher. Thus all women and men with lupus should be told that infertility is a possible consequence of cyclophosphamide treatment. They should also be aware that this drug causes congenital abnormalities and they must use reliable forms of contraception while on a course of cylophosphamide and for 3 months afterwards (see below).
Some people think that anti-phospholipid antibodies can cause infertility. However, there is no evidence that these antibodies interfere with fertility. They can cause blood clots ("sticky" blood or thrombosis) and, in pregnant women, miscarriages and stillbirths (see below).
Antibodies and pregnancy
(i) Antinuclear antibodies and anti-dsDNA antibodies
One of the hallmarks of lupus is the presence of antibodies in the blood that are recognise the body's own components. These antibodies are known as autoantibodies. Antinuclear antibodies are very common in lupus (over 95% of patients have them but they can occur in other diseases). They are often used to help make the diagnosis of lupus but they do not have any effect on pregnancy. Similarly, anti-DNA antibodies which are very typical of lupus do not themselves affect pregnancy but they are a marker of patients at increased risk of kidney disease and this can be associated with problems in pregnancy (see below).
(ii) Anti-phospholipid antibodies
As mentioned above the presence of anti-phospholipid antibodies is very important when considering pregnancy. These antibodies can be measured in 2 main ways: as anti-cardiolipin antibodies or as an abnormality on a clotting test known as "lupus anticoagulant". This is a strange term for an antibody which is associated with an increased risk of blood clots (thrombosis), as such complications actually need treatment with anticoagulants to make the blood thinner. However, the name reflects the observation that during the process of testing blood clotting in a laboratory, these antibodies interfere with the test by binding phospholipids needed to make blood clot in a test tube. This makes it look as if the blood is already anticoagulated (thinned). However, in real life the blood is at risk of clotting and this causes blood clots in the afterbirth that can predispose to poor growth of the baby, spontaneous miscarriages (loss of the baby up to 24 weeks) and stillbirths (delivery of babies that have died after 24 weeks).
Anti-phospholipid antibodies can also increase the risk of other types of blood clots such as deep vein thrombosis in the calf, pulmonary embolus (a blood clot on the lung) or stroke. All women are at increased risk of blood clots during pregnancy, due to the effects of oestrogen hormones on blood clotting. Similarly women are at some increased risk of blood clots while on oral contraceptive pills containing oestrogen hormones and these should be avoided in women with anti-phospholipid antibodies who are at increased risk of clotting even without the extra oestrogens associated with pregnancy or the contraceptive pill. Depending on the patient's history women with anti-phospholipid antibodies may be treated with aspirin, subcutaneous heparin injections or both in pregnancy to prevent blood clots and to prevent impairment of fetal growth due to placental dysfunction (poorly functioning afterbirth). Warfarin should be stopped as it can cause congenital abnormalities, particularly from 6-12 weeks.
(iii) Anti-Ro and anti-La antibodies
The other group of antibodies associated with complications in pregnancy are known as anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB). These antibodies are part of a group of antibodies that recognise proteins known as extractable nuclear antigens (ENAs). Anti-Ro and anti-La antibodies may occur together or separately. There is about a 1 in 100 risk that a baby born to a mother with either or both antibodies will develop congenital heart block. This is a permanent condition that usually requires the child to have a pacemaker inserted to control the heart rate. In about one third of cases this is needed in the first month and most of the remainder are put into the child by the age 12. Congenital heart block is usually detected between weeks 16 and 28 of the pregnancy, but occasionally it is picked up later. This is most likely if the mother is not known to have these antibodies prior to pregnancy and is not having the fetal heart rate monitored on a weekly basis. Several treatments have been given to mothers in pregnancy to try and treat babies that have developed congenital heart block, including high dose steroids (dexamethasone not prednisolone), plasma exchange and intravenous gamma globulins. Unfortunately there is no evidence that any of these definitely work at reversing heart block or preventing it in the next pregnancy. There is some evidence that dexamethasone may reverse partial heart block but it is still not clear how long the effects last. The risk of a subsequent baby developing heart block is about one in five.
There is also a risk that the baby born to a mother with these antibodies will develop a condition known as neonatal lupus syndrome. This typically presents with a rash, often a few weeks after birth. The baby's rash may be triggered by sunlight as in women with SLE, so babies born to mothers with lupus and these antibodies should not be placed in sunlight after birth. An affected baby may have mildly abnormal liver function tests and occasionally low platelets as well but this rarely causes bleeding. Neonatal lupus rash and syndrome occurs in the babies of about 1 in 30 women with anti-Ro and/or anti-La antibodies. The condition usually settles by itself without any special treatment except avoiding sunlight over a few weeks, as the baby gradually destroys the antibodies transferred during pregnancy from the mother to the baby. It is rare for these antibodies to cause any problems more than 6 months after the birth of the baby, unless the baby is born with congenital heart block or partial heart block.
Lupus pregnancy and blood pressure
Women with lupus who have a history of high blood pressure, kidney disease, anti-phospholipid antibodies or are on steroids are at increased risk of high blood pressure in pregnancy. Prednisolone doses up to 10 mg daily are not usually a problem. Higher doses can be given but in such cases the blood pressure should be monitored very carefully. Nifedipine is the drug that is most often used in pregnancy if therapy is needed to control the blood pressure. Labetalol is also used in some patients, particularly if nifedipine is not enough to keep the blood pressure at the desired level. Pre-eclampsia is a particular complication of pregnancy that consists of high blood pressure, painless ankle swelling due to fluid accumulation (oedema) and protein in the urine. This condition can progress to seriously high blood pressure in the mother with a risk of developing eclampsia, a more serious and fortunately rare condition that may involve epileptic fits, stroke and kidney failure. It can also affect how the placenta works. Consequently the baby may stop growing normally and in some cases may die causing a miscarriage or stillbirth (depending on the stage of pregnancy). As a result, a pregnant woman with high blood pressure that does not settle easily at home is usually brought in to hospital for observation (of mother and baby) and therapy. Treatment consists of bed rest, drug therapy and it may become necessary to deliver the baby, as this can be the only way to control the blood pressure, prevent progression of pre-eclampsia to eclampsia, and to avoid stillbirth.
Premature and full term delivery
Women with lupus are often able to deliver normally: that is a vaginal delivery between 38 and 42 weeks (full term). However, there is an increased risk of spontaneous early delivery (for example from 34 weeks onwards) and of late stillbirths after 40 weeks, although both of these complications are rare (about 2% of pregnancies). There is also an increased risk of premature rupture of membranes which leads to early delivery, either spontaneously or as a result of induction of labour, due to the risk of infection (especially in women on steroids). Finally some women undergo induction of labour or caesarian section due to poor fetal growth, reduced fetal movements and concern that the baby might die in the womb. These complications are more common in women that develop pre-eclampsia and/or have anti-phospholipid antibodies. Special care baby units may be the safest place for a baby if it is not doing well inside the mother and the obstetric team will carefully balance the risks of an early delivery against the risks of not delivering a baby. Similarly, a woman who has not gone into labour by 39 weeks will be assessed and if appropriate may have labour induced to avoid the small but real risk of a late stillbirth. Special plans for delivery may need to be made for women with a history of heart or lung disease, as the mother may have medical complications in the last weeks of pregnancy or during delivery.
Lupus flare in and after pregnancy
Most patients with lupus are advised not to become pregnant until the lupus is well controlled on drugs that can be continued in pregnancy. Drugs such as methotrexate, mycophenolate and cyclophosphamide must be stopped at least 3 months before pregnancy occurs. However, prednisolone, azathioprine and hydroxychloroquine are usually considered safe in pregnancy, particularly at low doses. Providing that the lupus is controlled at the beginning of pregnancy, the risk of lupus flare is low in pregnancy and highest after the delivery. If the lupus is grumbling or clearly active at the start of pregnancy, the risks of disease deterioration are highest in the first and second trimestres (up to 24 weeks). Most flares are mild and respond to small changes in prednisolone. The highest risk of severe disease flares is in patients with a history of kidney disease, in whom pre-eclampsia can sometimes be difficult but important to distinguish. Lupus sometimes appears for the first time in pregnancy or in the first 3 months afterwards (post-partum). All lupus patients are at risk of a disease flare after delivery, probably because of the stress of the delivery and fatigue from looking after the newborn, combined with loss of the natural immunosuppressive effects of pregnancy which prevent the mother from physically rejecting the baby during pregnancy. It is important to plan in advance who will help care for the baby (and any other children), especially if the mother does become ill.
Conclusions
With modern treatment most women with lupus can have babies without serious problems for them or their babies. However, women who are planning pregnancy should ensure that the doctors think that their disease is well controlled and that they are on appropriate drugs before they become pregnant. The issue of appropriate drug therapy also applies to men with lupus hoping to father babies. Women with a history of renal and heart or lung disease should obtain specialist advice from their physician and obstetrician before they become pregnant, especially if their kidney, heart or lung function is reduced, they are on dialysis or post-transplant. A physician and obstetrician should also be involved in assessing patients with anti-phospholipid antibodies prior to pregnancy, so that a plan is made about what treatment they will need in pregnancy, when to stop warfarin if relevant and how to obtain subcutaneous injections of heparin if indicated. Plans for monitoring the fetal heart rate weekly from 16 weeks should be made for women with anti-ro and/or anti-la antibodies. Finally, thought needs to be given before pregnancy as to who will help the mother look after her newborn baby and any other children, as lupus patients often suffer from severe fatigue even without children or newborn babies to look after. Contraception should be discussed soon after delivery as the last thing a lupus patient with a newborn baby needs is another pregnancy. Plans for the next pregnancy should be discussed a later stage, when the full impact of the effects of this pregnancy can be appreciated.
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