Abstract

Pregnancy is an issue that should be discussed with all patients with rheumatic diseases who are in the reproductive age group. Infertility is rarely due to the disease but can be associated with cyclophosphamide therapy. Most rheumatic diseases that are well controlled prior to pregnancy do not deteriorate in pregnancy, providing that the patient continues with appropriate disease-modifying therapy. Some patients with inflammatory arthritis go in to remission during pregnancy. Patients with renal involvement may be at increased risk of disease flare. This needs to be distinguished from pre-eclampsia. Intrauterine growth restriction is more likely in patients with active systemic disease, hypertension, a history of thrombosis and renal involvement. Premature delivery may need to be planned to reduce the risks of stillbirth and can be associated with a variety of neonatal complications. Post-partum flare is common in all the rheumatic diseases.

Introduction

In the past, women with rheumatic diseases were advised against pregnancy due to maternal and fetal morbidity and mortality and the complex influence of sex hormones on immunity. Recently, however, it has been found that with good disease control and rigorous monitoring, there is no reason why the majority of these women should not have the opportunity to bear children.

This review aims to discuss the maternal and fetal effects of pregnancy in systemic lupus erythematosus (SLE), Sjögren's syndrome, anti-phospholipid syndrome (APS), rheumatoid arthritis (RA), spondylarthropathies, the vasculitides and systemic sclerosis. The review will be divided into four sections. The first will be the effect of rheumatic diseases in the mother on fertility, followed by the effects of pregnancy on the disease, then the risk of transmission of disease from mother to foetus, and finally fetal outcome in the different rheumatic diseases. Therapy for these diseases during pregnancy will not be discussed but the reader is recommended to read an excellent review by Ostensen et al. [1]. It should be noted that there is a paucity of controlled studies addressing the prevalence of the complications discussed, and that most of the observations are from cohort studies or case series. The most important maternal and fetal complications of the rheumatic diseases discussed are shown in the Table 1.

Table 1.

The most important maternal and fetal complications associated with pregnancy in rheumatic diseases

Rheumatic disease Maternal Complications Fetal Complications 
SLE Reduced fertility most associated with cyclophosphamide treatment Rash due to neonatal lupus syndrome 
 Increased risk of lupus flare & ovarian hyperstimulation with IVF & ovulation induction Congenital complete heart block 
 Flare during pregnancy and postpartum IUGR 
 Hypertention Fetal loss 
 Pre-eclampsia Premature delivery 
 HELLP  
 Increased risk of Caesarean section  
Sjögren's syndrome Flare during pregnancy and postpartum Rash due to neonatal lupus syndrome 
  Congenital complete heart block 
APS Thrombosis IUGR 
 Pre-eclampsia Fetal loss 
 Eclampsia Premature delivery 
 HELLP Neonatal thrombocytopenia 
 Thrombocytopenia Neonatal thrombosis (rare) 
RA Postpartum flare  
 New onset RA post pregnancy  
Spondylo-arthropathies Back pain less likely to improve than arthritis and may deteriorate  
 Postpartum flare  
Beçhet's syndrome Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Thrombosis Premature delivery 
 Flare  
Takayasu's disease Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
 Hypertension  
 Congestive cardiac failure  
 Renal impairement  
 Pre-eclampsia  
 Sepsis  
 Antepartum haemorrhage  
Wegener's granulomatosis Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
Churg-Strauss syndrome Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
Polyarteritis nodosa Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
 Increased mortality Neonatal cutaneous vasculitis (rare) 
Systemic sclerosis Deterioration in pulmonary hypertension Fetal loss 
 Mallory Weiss tear Premature delivery 
 Hypertension  
 Renal crisis  
 Postpartum flare  
Rheumatic disease Maternal Complications Fetal Complications 
SLE Reduced fertility most associated with cyclophosphamide treatment Rash due to neonatal lupus syndrome 
 Increased risk of lupus flare & ovarian hyperstimulation with IVF & ovulation induction Congenital complete heart block 
 Flare during pregnancy and postpartum IUGR 
 Hypertention Fetal loss 
 Pre-eclampsia Premature delivery 
 HELLP  
 Increased risk of Caesarean section  
Sjögren's syndrome Flare during pregnancy and postpartum Rash due to neonatal lupus syndrome 
  Congenital complete heart block 
APS Thrombosis IUGR 
 Pre-eclampsia Fetal loss 
 Eclampsia Premature delivery 
 HELLP Neonatal thrombocytopenia 
 Thrombocytopenia Neonatal thrombosis (rare) 
RA Postpartum flare  
 New onset RA post pregnancy  
Spondylo-arthropathies Back pain less likely to improve than arthritis and may deteriorate  
 Postpartum flare  
Beçhet's syndrome Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Thrombosis Premature delivery 
 Flare  
Takayasu's disease Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
 Hypertension  
 Congestive cardiac failure  
 Renal impairement  
 Pre-eclampsia  
 Sepsis  
 Antepartum haemorrhage  
Wegener's granulomatosis Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
Churg-Strauss syndrome Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
Polyarteritis nodosa Reduced fertility associated with cyclophosphamide treatment Fetal loss 
 Flare during pregnancy and postpartum Premature delivery 
 Increased mortality Neonatal cutaneous vasculitis (rare) 
Systemic sclerosis Deterioration in pulmonary hypertension Fetal loss 
 Mallory Weiss tear Premature delivery 
 Hypertension  
 Renal crisis  
 Postpartum flare  

IUGR, Intra-Uterine Growth Restriction; HELLP, Haemolysis, Elevated Liver Enzymes, Low Platelets.

Fertility

SLE, RA, the vasculitides and the spondyloarthropathies are not known to directly affect fertility. Although SLE patients are as fertile as the general population, with a reported pregnancy rate of 2.0 to 2.4 pregnancies per patient during remission and active disease, studies comparing fertility before and after a diagnosis of SLE have found that fertility dropped significantly when compared with the control group, from 3.4% to 2.1% [2]. There is a reported reduced fertility rate in patients with active disease who are treated with high dose corticosteroid therapy, as menstrual irregularities and anovulatory cycles may occur. End-stage renal failure secondary to lupus nephritis can result in amenorrhoea [3]. Amenorrhoea in renal patients may also be due to ovarian failure secondary to cyclophosphamide or it may be of autoimmune origin.

The risk of ovarian failure in SLE and vasculitis patients due to cyclophosphamide therapy is dependant on the route of administration, age of the woman at the start of therapy and the cumulative dose of cyclophosphamide [3, 4]. Females under the age of 26 yrs including prepubertal girls are less likely to develop premature ovarian failure than women who start cyclophosphamide treatment at a later age [4]. The reported frequency of premature ovarian failure in patients receiving cyclophosphamide treatment for severe lupus nephritis over the last two decades has ranged from 11 to 59% [3]. Although not often used, a recent study showed that treatment with synthetic Gonadotropin Releasing Hormone (GnRH) whilst receiving cyclophosphamide significantly reduced the risk of premature ovarian failure, as only 5% of the GnRH-treated group developed ovarian failure, in contrast to 30% of the control group [5]. Further efforts at preserving fertility in women receiving cyclophosphamide therapy have been tried using the combined oral contraceptive, but there has been no supportive data and it may increase the risk of flares in lupus patients [5].

Although APS is not generally thought to cause infertility, antiphospholipid antibodies may be associated with infertility but the precise underlying mechanism has yet to be determined [6, 7]. APS is also associated with a risk of ovarian vein thrombosis, which can affect fertility [8].

There is no direct evidence that primary Sjögren's syndrome is associated with a reduced fertility rate, but an association between endometriosis and Sjögren's syndrome has been demonstrated, which may affect fertility depending on severity [9]. In one study, 5.9% of women affected with primary Sjögren's syndrome chose not to have children due to their connective tissue disease, but those who made the decision to have children were not found to have a reduced fertility rate, which concords with previous studies [9, 10]. There is no evidence that there is a significant difference in fertility between healthy controls and systemic sclerosis [11], but as with primary Sjögren's syndrome, there are few data as women often present after the reproductive period.

Ovulation induction

Ovulation induction and in vitro fertilization (IVF) have provided further insight into how hormonal manipulation can affect rheumatic diseases such as SLE and APS. There is a reported increased risk fetal and maternal complications when undergoing ovulation induction and IVF, such as lupus flares and ovarian hyper stimulation that has led some women to opt for surrogacy [6]. There is also a risk of thrombosis in women with APS undergoing ovarian induction [12], associated with the oestrogen surge but this is less than that associated with the levels of oestrogen in later pregnancy [13]. Thus women should be counselled appropriately of these risks before embarking on ovulation induction.

Effect of pregnancy on autoimmune diseases in the mother

SLE

(a) Flares

There is no consensus on whether or not pregnancy increases the risk of lupus flares in pregnancy, but until recently pregnancy was considered to aggravate lupus disease activity. However, in the past, many patients used to stop all their therapy upon discovering that they were pregnant, which may have contributed to an increased risk of flare in pregnancy.

Appropriate counselling on treatment regimens, prior to conception and during pregnancy is essential. Studies have produced contradictory results as to whether lupus flare is more common in pregnancy than in non-pregnant state or not. This may be explained by differences in the definition of lupus flare, assessment of disease activity, and differentiation between lupus flare and pregnancy associated complications or physiological changes of pregnancy [14, 15]. In order to overcome this situation, recent research has been directed at developing standardized methods of assessing disease activity in pregnancy [16]. The lupus activity index in pregnancy (LAI-P) has been validated [17] and a version of BILAG-2004 [18] for use in pregnancy is currently being developed. Studies demonstrating an increase in flares during pregnancy and 3 months postpartum when compared with non-pregnant lupus patients in a 12-month period, showed that most flares were mild and responsive to low dose steroids, hydroxychloroquine and or azathioprine [14, 15]. SLE can flare at any point in the pregnancy or postpartum period. It has demonstrated that if the disease is inactive at conception then the risk of flares is reduced, in comparison with both those who had active disease at conception and the non-pregnant controls [19]. It is important to be aware of the risk of pulmonary hypertension in lupus as, despite it being rare, there is a 50% mortality rate in pregnancy [20].

Cortico-steroids are used to control active lupus during pregnancy. Prednisolone is mainly metabolized, meaning that very little crosses the placenta in doses up to 20 mg daily so that adrenal neonatal suppression is rare. In severe cases methylprednisolone pulses may be given. However, it is important to maintain the minimum possible dose as, with doses above 10 mg daily, steroids can associated with an increased risk of pre-eclampsia, pregnancy induced hypertension, gestational diabetes, infection and possible premature rupture of membranes [14]. Further discussion about the safety of drugs used to control disease activity in pregnancy can be found in the comprehensive review by Ostensen et al. [1]

(b) Hypertension

A higher rate of adverse obstetric outcome has been demonstrated in women with SLE and hypertension. For example in hypertensive patients, there is a three-fold higher rate of intra-uterine growth restriction (IUGR). Nearly 25% of pregnancies in women with SLE are complicated by hypertensive disorders and there is also a higher rate of caesarean sections than in the control population [21]. Hypertension is more common in pregnant patients on corticosteroids and in patients with a history of lupus nephritis than in controls.

(c) Renal lupus

Renal involvement in SLE is an important aspect of managing all SLE patients as the kidney is one of the major target organs and up to 60% of patients experience focal or diffuse renal involvement at some point in the disease course [22]. Renal lupus is characterized by the following features: proteinuria greater than 500 mg/24 h, haematuria, red cell casts and hypertension. Proteinuria without the presence of red cells or casts in the urine can be difficult to distinguish from pre-eclampsia. There is usually extra-renal active disease at the same time and the laboratory tests show increasing anti-dsDNA antibodies and falling complement C3 and C4 levels with active lupus nephritis. Active lupus nephritis is a contraindication for pregnancy as it is associated with poor fetal outcome as well as maternal complications. It is recommended that that conception should be planned at least 6 months after induction of remission to reduce the risk of pregnancy exacerbating lupus nephritis. Remission in lupus nephritis has been defined as stable renal function, a serum creatinine within the normal range, urinary red cells below 5/high power field, proteinuria below 0.5 g/day and ideally normal serum C3 levels for 12–18 months [3, 23, 24]. Once pregnancy has occurred, patients should be followed up by a multi-disciplinary team, so that all aspects of the disease and the pregnancy can be managed most efficiently and safely for the mother and baby.

(d) Pre-eclampsia

Although pre-eclampsia and lupus nephritis may co-exist in pregnancy, it is essential to differentiate isolated pre-eclampsia from renal lupus during pregnancy, as management will be very different depending on the diagnosis. Pre-eclampsia can be defined as blood pressure over 140/90 or the rise of 30 mmHg systolic or 15 mmHg diastolic in combination with proteinuria (>300 mg/24 h) and oedema at greater than 20 weeks gestation. Serologically the complement levels C3 and C4, will characteristically fall by 25% with active renal involvement, in contrast to the 10–15% rise seen in normal pregnancy and pre-eclampsia [14, 16, 25]. If the proteinuria is of recent onset and associated with hypertension, or there is a previous history of pre-eclampsia, hypertension or antiphospholipid syndrome, proteinuria is more likely to be due to pre-eclampsia than lupus nephritis [3, 14, 16]. Lupus nephritis is more likely if there is a positive urinary sediment (cells and/or casts in the urine in the absence of other causes of red or white cells). Pre-eclampsia is also more likely if associated with features of the HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome, but again it is important to differentiate this from active lupus nephritis, as steroids are necessary to treat lupus nephritis but will aggravate pre-eclampsia. The ultimate treatment for pre-eclampsia is delivery of the fetus, although anti-hypertensives may be tried initially.

Sjögren's syndrome

Although there are very few data in the literature, it has previously been observed that, as with SLE, providing that the disease is well controlled at conception, the prognosis is good. It is important to maintain appropriate therapy, such as low dose steroids, hydroxychloroquine and/or azathioprine if being used before pregnancy, and to avoid conception during active disease, as with SLE and vasculitis [14].

Anti-phospholipid syndrome

(a) Thrombosis

All women are in a prothrombotic state during pregnancy and for 6 weeks postpartum and so are at increased risk of deep vein thrombosis, pulmonary emboli and stroke, irrespective of the presence or absence of antiphospholipid antibodies [14, 26]. APS has been shown to increase the risk of all types of arterial and venous thrombosis in pregnancy, not just deep vein thrombosis and pulmonary emboli. A higher pregnancy success rate has been shown in women with APS and recurrent miscarriages taking low dose aspirin in pregnancy [27], but this may not be sufficient for women with a history of recurrent miscarriages and with a history of thrombo-embolism, pre-eclampsia or stillbirth [14, 26]. These patients are likely to require subcutaneous heparin. The optimal anti-thrombotic dose regime is dependant on the precise history of fetal loss and thrombosis [1, 14, 26]. It is also important to consider the risk of osteoporosis in women treated with heparin [28], particularly in women taking steroids as well for SLE.

(b) Pre-eclampsia

Pre-eclampsia is most common in pregnancies where the mother has APS. In patients with APS, it often recurs and may present as very early onset pre-eclampsia (<20 weeks) [29, 30]). Pre-eclampsia, is associated with uteroplacental insufficiency, caused by multiple placental thromboses, infarcts and a spinal artery vasculopathy in decidual vessels [31]. Although pre-eclampsia can be treated with bed rest and anti-hypertensives, in resistant cases the fetus should be delivered before progression to the more serious condition of eclampsia and the risk of fetal death. Eclampsia can be defined as a hypertensive crisis, associated with fits and a risk of coma. It is treated supportively to stabilize the epileptic fits and hypertension, but the definitive treatment is delivery of the fetus. Patients with APS also have an increased incidence and severity of the HELLP syndrome than the general population [32], with or without pre-eclampsia or eclampsia. HELLP is usually treated by supportive care, steroids and delivery, but remission has been observed after plasma exchange in APS [32]. Occasionally, HELLP persists or presents for the first time in the postpartum period.

(c) Thombocytopenia

It should be noted that thrombocytopenia may occur for a variety of reasons in pregnancy. Although APS, lupus or HELLP are the best known associations in patients with rheumatic diseases, it should not be forgotten that approximately 9% of healthy women develop mild thrombocytopenia for non-autoimmune reasons. Isolated anti-platelet antibodies can cause an idiopathic thrombocytopenia. Thrombocytopenia associated with APS may worsen in pregnancy or due to treatment with heparin. However APS is more often the cause than heparin in patients with antiphospholipid antibodies [14]. The risk of heparin-induced thrombocytopenia can be reduced by using low-molecular weight heparin rather than unfractionated heparin. These two drugs are of equal effectiveness at preventing APS related pregnancy loss and thrombosis [33]. Worsening thrombocytopenia has been documented to herald the onset of thrombosis in APS patients, so the recommended management is dependant on the factor Xa levels. If the platelet count falls and the factor Xa level is found to indicate over anticoagulation with heparin, it is best to stop the heparin. If the factor Xa level is found to be in the target region or low, the heparin dose should only be reduced if there are any signs of bleeding or there is other evidence of heparin toxicity.

Rheumatoid arthritis

In contrast to SLE, RA has been known to improve during pregnancy for many years. Several studies have shown significant improvement in 75–95% of pregnant women with RA. The improvement commences in the first trimester and improves maximally in the last semester [34, 35]. The discrepancy between RA and SLE in pregnancy is thought to be due to the differences in autoimmune response. Part of the mechanism for the induction of remission during pregnancy is likely to be mediated by the effect of endogenous female hormones on cytokines influencing disease activity [36]. SLE is characterized by a predominantly humoral response (Th2 type) response whereas RA is thought to be provoked by a more cellular response (Th1 type) [37]. It is known that in pregnancy there is a raised Th2 type response, in comparison with the non-pregnant state, leading to over expression of Th2 cytokines, such as IL-4 and IL-10. IL-10 is believed to increase autoantibody response in SLE but to be immunosuppressive in RA [38]. There is recent evidence that not only is there a Th2 type of response in pregnancy, but in fact complex immunomodulation at the maternal–fetal interface occurs. This has systemic effects in the maternal circulation, dependent on the stage of pregnancy [35, 39]. Another contributing cause to the remission of RA in pregnancy may be the depression of polymorph nuclear neutrophil function in the synovial fluid by alpha fetoprotein, which reduces the degree of synovial fluid inflammation [40].

During the postpartum period it is common for RA to flare. In addition, new-onset RA has been reported to be 3–5 times more frequent at this time [41, 42]. The precise aetiology for this phenomenon is unknown. It has been suggested that it may due to the increase of prolactin levels associated with breast-feeding as this hormone is pro-inflammatory, but there is conflicting views on this and the loss of pregnancy related immunomodulatory hormones may be sufficient to explain the observation. It has also been demonstrated that the long-term outcome of RA in terms of joint damage and disability, is minimally affected by pregnancy and oral contraceptive use, which is important when counselling women regarding pregnancy and contraception [36]. It has also been found that there is an increased risk of RA developing in women who have had adverse pregnancy outcomes, miscarriage, termination or stillbirth. These complications may increase the risk of RA, but conversely there is no reported increase of adverse pregnancy outcomes in RA [34]. However, a link has been found between miscarriage and the severity of RA. Women with at least one miscarriage have been found to have had an increased rate of joint damage [43].

Spondyloarthropathy

Although there are much fewer data than for RA, pregnancy has been demonstrated to significantly improve peripheral arthritis (as with RA) and uveitis in most patients, but in 25% of patients with predominantly spinal disease it deteriorates in pregnancy. It is difficult to differentiate whether this is due to inflammatory or mechanical changes in pregnancy [44]. During pregnancy there is a change in posture and spinal mobility, partially initiated by relaxin and other hormonal changes during gestation, which cause ligament relaxation. As with other rheumatic disease there is an increased risk of flare postpartum.

Vasculitides

In contrast to RA and SLE, the vasculitides are commoner in men then women and tend to occur in an older age group, so they rarely complicate pregnancy. The data that exists is mostly from small case series in contrast to the cohort studies available for RA, SLE and even systemic sclerosis. Takayasu's disease is the most commonly seen vasculitis in pregnancy, excluding idiopathic vasculitis and the vasculitis of SLE, and it is associated with hypertension, congestive heart failure and renal failure. Takayasu's disease has also been complicated in pregnancy by pre-eclampsia, antepartum haemorrhage, stroke (thrombosis and bleed) and sepsis [14]. Proteinuria and haematuria usually indicate renal involvement, whereas hypertension followed by proteinuria usually indicates pre-eclampsia, similar to the situation in SLE.

In women with Beçhet's disease there is an increased risk of thrombosis due to both the disease process and pregnancy itself. Despite anticoagulation central venous thrombosis may occur and in these cases IV heparin should be initiated. Wegner's granulomatosis may present prior, during or after pregnancy in women of child bearing age [45]. The commonest time for flares is in the first or second trimester or postpartum. Steroids and azathioprine should be used to control disease. Cyclophosphamide is much more toxic and not usually recommended in pregnancy but flares of Wegner's granulomatosis have been successfully treated with cyclophosphamide during the third trimester of pregnancy. Polyarteritis nodosa (PAN) can occur during pregnancy or in the postpartum period and is associated with a high mortality. Churg–Strauss vasculitis is associated with flares in pregnancy and during the postpartum period [45].

With all vasculitides it is important to ensure that the disease is inactive prior to pregnancy as it has been observed that there is an increased risk of maternal and fetal mortality in pregnancies where newly diagnosed active or uncontrolled vasculitis is present [45]. It is important to distinguish pre-eclampsia from renal vasculitis. Proteinuria and haematuria is association with other features of vasculitis usually indicates active disease, whereas hypertension followed by proteinuria usually indicates pre-eclampsia similar to the situation in SLE.

Systemic sclerosis

Systemic sclerosis does not usually deteriorate during pregnancy, provided that the disease is stable at conception, but it may develop during pregnancy or the postpartum [11, 46]. The features of systemic sclerosis in pregnancy are very similar to those described by healthy pregnant women, including gastro-oesophageal reflux disease and shortness of breath on exertion [46]. The shortness of breath on exertion is particularly worse in the third semester as the uterus enlarges, but it is important to rule out pulmonary hypertension during pre-conception counselling, as it is a contraindication to pregnancy due to the associated 50% risk of maternal death in all causes of pulmonary hypertension irrespective of underlying cause. Women with oesophageal disease who vomit during pregnancy have experienced Mallory–Weiss tears. This can be associated with life-threatening bleeding and recurrent vomiting that requires prompt hospital care. The second half of pregnancy is associated with a physiological increase in cardiac output, which usually results in an improvement in the Raynaud's phenomenon. Skin manifestations in systemic sclerosis usually improve during pregnancy, but there is often a deterioration in sclerodermatous skin changes in the post-natal period [11, 46].

Hypertension in systemic sclerosis can lead to a renal crisis. This is the greatest risk to mother and baby, especially as it is difficult to identify and treat, and mimics the presentation of pre-eclampsia and HELLP syndrome. However, a systemic sclerosis renal crisis can be differentiated by the daily increases in creatinine levels and an absence of proteinuria, whereas the HELLP syndrome is usually characterized by elevated liver function tests, proteinuria and oedema [11, 46]. Renal crisis has been reported to be commoner in patients who have had systemic sclerosis for less than 5 yrs. ACE inhibitors are a life-saving treatment in hypertensive renal crisis in patients with systemic sclerosis despite their association with congenital malformations and kidney dysfunction in the infant [46]. In contrast to pre-eclampsia, delivery does not affect the hypertension or renal crisis seen in systemic sclerosis. If a woman has experienced a renal crisis during a previous pregnancy, she should avoid pregnancy until disease has been stabilized, which is usually 3–5 yrs from the onset of symptoms. These women are usually treated with nifedipine to maintain blood pressure control, but delivery is usually recommended if appropriate antihypertensives fail. ACE inhibitors may be initiated during pregnancy in severe cases after appropriate counselling about the risk of congenital abnormalities [46].

Risk of transmission from mother to fetus

SLE and Sjögren's syndrome are the most widely recognized rheumatic diseases in which pathogenic antibodies can pass from mother to infant through the transmission of anti-Ro and/or anti-La across the placenta during pregnancy (see subsequent text). [47]. The prevalence of these auto-antibodies in SLE patient is about 35% but transmission of IgG antibodies across the placenta between weeks 16 and 32 gestation occurs in about 5% of mothers [47, 48]. Neonatal transmission usually resolves within the first 6 months of life, as maternal antibodies are destroyed in the infant.

Neonatal cutaneous vasculitis has been reported in the infants of mothers with cutaneous PAN due to the transmission of auto-antibodies, but the condition resolved soon after birth [45]. A leucocytoclastic vasculitis has been reported in the newborn following a history of a vasculitis which worsened throughout pregnancy and postpartum in the mother [14]. Finally, neonatal thrombocytopenia is recognized to occur in infants, due to the transmission of anti-platelet antibodies across the placenta in mothers with APS. However, thrombotic complications in the neonate are rare.

Neonatal lupus syndrome occurs due to the transmission of maternal auto antibodies across the placenta from week 16. It may present as transient cutaneous lupus lesions, complete heart block, cytopenia, hepatic and other manifestations, occurring in infants born to mothers with positive anti-Ro or anti-La antibodies [48]. Neonatal lupus rash is the most common manifestation and usually presents within a few weeks of birth and is often induced by exposure to UV light. The lesions are typically annular or elliptical with erythema and scaling, similar to those seen in adults with subacute cutaneous lupus. They usually persist several weeks or even a few months, resolving as the maternal autoantibodies are cleared from the fetal circulation.

The most severe complication of neonatal lupus syndrome is congenital heart block (CHB). Complete CHB is diagnosed when fetal bradycardia is identified usually between 18 and 28 weeks. It is important to closely monitor these pregnancies by serial doppler echocardiography. Measurement of AV time intervals is a suggested surveillance instrument, as incomplete block may progress in utero or post-delivery and carries a 20% mortality rate. Permanent pacemakers are required by 67% of survivors with complete CHB [48]. Dexamethasone or betamethasone may be given to try and reverse heart block, as it is able to cross the placenta unlike prednisolone [1]. First and second degree heart bock and heart failure due to myocarditis may be reversed but there is no evidence for reversal of third degree heart block [48]. Affected fetuses should be referred to a paediatric cardiologist for close monitoring.

It is vital to identify maternal anti Ro/La status prior to conception or in early pregnancy. The mother may or may not have a history of photosensitive rash herself treated with hydroxychloroquine. It is not known if this drug has any influence on the development of neonatal lupus syndrome but it appears to be safe in pregnancy [49, 50]. The fetal heart rate should be assessed on a weekly basis from week 16 by the midwife or obstetric unit and close monitoring by ultrasound can be considered from week 16 to week 28 [50]. Thus heart block can be identified as early as possible and treatment can be initiated if necessary. It is also important to be aware that approximately half the cases of neonatal lupus will occur in pregnancies where the woman has not been diagnosed with a connective tissue disease. At least half of these women will develop Sjögren's syndrome or lupus over the next 10 yrs [14, 48].

Fetal outcome

Fetal loss

Pregnancies in SLE patients are associated with a greater risk of still births, abortions and premature delivery than in the general population [15, 51]. The risk is increased in women who have previously experienced fetal loss, active renal disease at conception, maternal hypertension and the presence of anti-phospholipid antibodies. Recurrent fetal loss is also one of the criteria when diagnosing APS and the presence of both lupus anticoagulant and anticardiolipin antibodies is associated with the highest risk of fetal loss.

Intrauterine growth restriction

The risk of IUGR is increased in pregnancies with a maternal diagnosis of SLE and APS despite adjustment for maternal ethnicity [21]. In SLE patients, hypertension, active lupus and APS are significant predictive factors for IUGR [14, 50, 52, 53]. Fetal loss in early pregnancy in APS can be due to failure of the placenta to implant, due to the effect of anti-phospholipid antibodies on anionic phospholipids and the effect of B2-glycoprotein on trophoblasts. Thrombosis in APS is also thought to have a role in pregnancy loss due to uteroplacental insufficiency from multiple placental thromboses and infarcts [31]. A good predictor of adverse pregnancy outcome is doppler ultrasound examination during the second trimester. An abnormal uterine artery wave form has been shown to be a predictor of fetal or neonatal death [54]. The use of aspirin and heparin in pregnancy probably reduces miscarriages by an antithrombotic mechanism, as well as by preventing pathological apoptosis and anti-complement effects [55].

Premature delivery

Premature delivery is common in patients with lupus, vasculitis, systemic sclerosis and especially antiphospholipid syndrome [26, 45, 46, 52, 56]. Premature delivery has been found to occur in up to 55% of SLE and vasculitis pregnancies. Fetal outcome, in terms of IUGR, prematurity and fetal loss were more favourable in patient with a past history of lupus nephritis if the patients renal function is normal, blood pressure is controlled and there is no significant proteinuria at conception.

There are several complications of prematurity, regardless of underlying cause, such as breathing difficulties, infection, jaundice, feeding difficulties, developmental abnormalities and neonatal death. Breathing difficulties are usually due to insufficient surfactant, which can be reduced by a 48-h course of dexamethsone or betamethasone in cases where there is a high chance of premature delivery, such as active maternal disease or fetal distress. Although prematurity and neonatal problems are common in children born to women with APS, the long-term childhood course has been found to be similar to that of other premature infants [57]. It has also been found that the children born to mothers with lupus, have a similar incidence of minor physical abnormalities as that of the general population in a small US study [58].

Summary

Pregnancies in women with rheumatic diseases require a multi-disciplinary, carefully monitored, coordinated approach before, during and after pregnancy to ensure the best possible success for mother and baby. In contrast to SLE, APS, vasculitis and systemic sclerosis there is little evidence for poor maternal or fetal outcomes in RA or other forms of inflammatory arthritis such as psoriasis and seronegative spondyloarthropathies. Prior to pregnancy it is important to counsel the mother concerning potential complications, establish disease activity control, screen for hypertension and renal involvement, exclude pulmonary hypertension and make appropriate changes to the woman's therapy. During pregnancy it is essential to monitor all aspects of disease activity such as renal involvement, as well as pregnancy complications such as IUGR, thrombo-embolic disease and pre-eclampsia, particularly in patients with SLE, APS, vasculitis and systemic sclerosis. After pregnancy it is essential to counsel the mother on postpartum issues such as breast-feeding and contraception, as well as to monitor for and treat any postpartum flares as these are common in all the rheumatic diseases.

graphic

Disclosure statement: The authors have declared no conflicts of interest.

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