7 Systemic sclerosis and pregnancy CAROL

M. BLACK

Systemic sclerosis (scleroderma, SSc) is a multisystem, female-dominated disease of unknown aetiology. It is characterized by the overproduction and growth of what appears to be normal connective tissue, along with widespread vascular damage and the development of microvascular obliteration (Seibold, 1989; Carpentier and Maricq, 1990). The pathogenesis, although uncertain, almost certainly includes inflammation, immune dysfunction, endothelial damage, and cytokine and growth factor activation of the connective tissue. Pregnancy is also a systemic condition requiring growth and profound changes in hormonal regulation, the maternal immune system and the vasculature and connective tissue. In the event of the two occurring together it would be expected that SSc might have a major impact on pregnancy and vice versa. The problem is that SSc is an uncommon heterogeneous condition and pregnancy in established SSc an infrequent event; our knowledge of the interaction of these two conditions is therefore minimal, often anecdotal and, to date, retrospective. It is evident that the management of the patient with SSc who is pregnant, or who wishes to become so, presents challenges that require in-depth knowledge from both physician and obstetrician of the clinical heterogeneity, pathophysiology, immune changes and approaches to therapy in both conditions. The intention of this chapter is to summarize briefly current concepts about the aetiology and pathogenesis of SSc, review the relationship between SSc and pregnancy, and suggest an approach to the management of pregnant women with SSc in the antepartum, partum and postpartum periods. Scleroderma is an uncommon condition. Epidemiological studies (Silman et al, 1988; Maricq et al, 1989) have yielded estimates of prevalence between 28 and 130 per million with an annual incidence of between 2.3 and 10 per million in the adult population. It is a disease with a predilection for females (O'Leary and Nomland, 1930; Tuffanelli, 1969; Eason et al, 1981; Medsger, 1985). The estimated female to male incidence varies with age, but among all ages is 3.0 in whites (3.6: 1.2) and 2.7 in blacks (4.3 : 1.6), rising to 10:1 in the age group 15-44, i.e. during the reproductive years (Masi, 1987). Sex is the strongest genetic marker for the disease, unfortunately as yet completely unexplored. Scleroderma is less common during the early reproductive period. Previously, this was the time when most women had their pregnancies Bailli~re's ClinicalRheumatology-Vol. 4, No. 1, April 1990 ISBN 0-7020-1481-8

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and therefore scleroderma usually presented after the birth of their children. However, recently there has been a trend towards pregnancies later in life (Stein, 1985) and therefore the co-occurrence of scleroderma and pregnancy may increase. Scleroderma is a heterogeneous disorder ranging from the presclerotic state, through mild disease with minimal organ involvement, to aggressive diffuse disease which is life-threatening. Classification is difficult but the most useful method devised to date is based on location, degree and extent of skin involvement, and a number of reliable clinical, laboratory and natural history associations with skin sclerosis have been made (Table 1). Although it is relatively easy to advise the woman with bad disease concerning the possible effects of pregnancy, the milder forms are much more difficult and the outcome for both mother and baby uncertain. The milder forms of the disorder are often difficult to identify, and Raynaud's phenomenon, a frequent forerunner and common disorder in women, can be easily ignored. The patient may only develop the full-blown clinical picture whilst pregnant, the previously dormant subclinical or minimal signs only becoming evident and progressive with the growing fetus. Unfortunately, this is most likely to occur in the third trimester, at birth, or postpartum--all high-risk periods. Thus the subject is fraught with uncertainty and confusion. The problem is compounded because, as previously mentioned, the co-occurrence of SSc and pregnancy is unusual and any one physician or obstetrician will meet only a small number of cases. Published work on scleroderma and pregnancy is scant and inadequate.

Table 1. Subsets of systemic sclerosis (SSc). Diffuse cutaneous SSc (dcSSc)*

Onset of Raynaud's within 1 year of onset of skin changes (puffy or hidebound) Truncal and acral skin involvement Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement Absence of anticentromere antibodies (ACA) Nailfold capillary dilatation and capillary destructiont Antitopoisomerase antibodies (30% of patients) Limited cutaneous SSc (IcSSc)

Raynaud's for years (occasionally decades) Skin involvement limited to hands, face, feet, and forearms (acral) or absent A significant late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcifications, telangiectasia A high incidence of ACA (70-80%) Dilated nailfold capillary loops, usually without capillary dropout * Experienced observers note some patients with dcSSc who do not develop organ insufficiency and suggest the term chronic dcSSc for these patients. + Nailford capillary dilatation and destruction may also be seen in patients with dermatomyositis, overlap syndromes, and undifferentiated connective tissue disease. These syndromes may be considered as part of the spectrum of scleroderma-associated disorders. From LeRoy et al (1988) with permission.

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There are single case reports, often reporting a complicated pregnancy with a poor outcome: few physicians report successful cases. There are a few large series and fortunately the late-1980s saw the publication of three case-controlled studies, albeit ones using retrospective data; a fourth is about to be published.

SSc: BACKGROUND AND CLINICAL RELATIONSHIP TO PREGNANCY Although the aetiology of SSc is still uncertain it is almost certainly multifactorial, with genetic and environmental factors playing a part (Black et al, 1983; Briggs et al, 1986; Black and Welsh, 1988a). As stated earlier, the strongest genetic marker is sex, and epidemiological, biological and human experimental data point to an influence, either direct or via other mediators such as 5-hydroxytryptamine or female sex hormones on vascular reactivity (Darton and Tooke, 1990). As most of the deterioration and catastrophes which may occur in the pregnant scleroderma patient relate to the vasculature (e.g. pulmonary hypertension, malignant hypertension and renal failure), there is an urgent need for careful investigation into the relationship between the hormones, femaleness, Raynaud's, SSc and other connective tissue diseases. Recent work has shown that there is an association between the major histocompatibility complex (MHC) class I, II and III HLA antigens which is strong but complex (Briggs et al, 1990). This involvement, together with the association of the T-cell receptor ~ gene with the disease (Kratz et al, 1989), strongly implicates a specific immune mechanism in SSc. There is no sound evidence for a general derangement of immune cell function (Lupoli et al, 1990) but the concept of a specific immune dysfunction is further supported by increased levels of interleukin-2 and interleukin-2 receptor found in the disease (Freundlich and Jimenez, 1987; Kahaleh and LeRoy, 1989) and the circulating antibodies Scl-70 and ACA seem to be against defined epitopes. In this respect the disease may be compared with systemic lupus erythematosus where only a restricted number of well-defined antibodies and their target epitopes are important. The stimulus/stimuli which induce the immune response are unknown in the idiopathic disease. To date, the only well-established animal model of an immune-mediated scleroderma-like disorder which may help us is that of chronic graft-versus-host disease in mice. There is also the human counterpart following bone marrow transplantation (Furst et al, 1979; Deeg and Storb, 1984; Janin-Mercier et al, 1984); the concept of a fetus or foreign graft initiating scleroderma in the mother or host will be discussed later in this chapter. Without the antigen, the nearest we can get to the primary disease event stems from the discovery of increased expression of c-myc and c-myb proto-oncogenes in the early active disease (Kahan et al, 1989). Fortunately, in environmentally induced SSc specific stimuli are known, e.g. vinyl chloride and epoxy resin, and, interestingly, the environmentally induced disease appears more prevalent in men. A major target for the immune

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response in SSc would appear to be the endothelium and current interest ranges from adhesion molecules to antibody, peptide and free radical induced damage (Korn, 1989). Naturally, anticardiolipin and anti-Ro (SS-A) antibodies, important to pregnancy and fetal loss in other connective tissue diseases, have been examined in SSc. Several series (Seibold et al, 1986; Rosenbaum et al, 1988; McHugh et al, 1989) have reported an absence of anticardiolipin antibodies, suggesting that the vascular damage is mediated via another mechanism and SSc has no known association with the neonatal lupus syndrome (Provost, 1983; Scott et al, 1983; McHugh et al, 1989). Although the pathogenesis of SSc is still uncertain, it is obvious that the development of the SSc lesion is complicated and involves events which may occur simultaneously or in sequence. These almost certainly include inflammation, autoimmune attack, vascular damage, cytokine and growth factor activation of fibroblasts and other cells, and interaction between different components of the extracellular matrix. The clinical effects of excess fibrosis and vascular damage are thickening of the skin, telangiectasia, digital ischaemia with ulcers and gangrene, contractures, muscle wasting, dysphagia, malabsorption, constipation, diarrhoea, cardiac arrhythmias, cardiac failure, pulmonary hypertension and renal failure. These processes considerably impair the normal physiological functions of many organs and can make the process of pregnancy difficult, as outlined in Table 2. The most dreaded complication is renal disease. The data to be presented later, particularly those from the single cases, will highlight the occurrence of renal involvement. It was the major cause of death in the scleroderma pregnancies reviewed and used to be the major cause of death in SSc itself (Cannon et al, 1974; Shapiro and Medsger, 1988; Black, 1990). The overall significance of renal disease prior to the mid-1970s, when the angiotensin converting enzyme (ACE) inhibitors were first used in SSc, was clearly demonstrated in the survival figures of Medsger et al (1971). In their first study 16 of 16 patients who developed renal scleroderma were dead within 1

Table 2. Possible difficultiesin pregnancy and postpartum. Malignant hypertension: renal failure Rapidly developingpulmonary hypertension Cardiac failure, myocarditis Muscle weakness, polymyositis Worsening dysphagia, oesophagitis, increased reflux Possible malnutrition and weight loss Additional constipation and increased incontinence Difficulties of venous access due to sclerosis of skin and flexioncontractures Sclerosis of lower legs, painful limbs, difficultyin walking Tight truncal skin, compressionof viscera Microstomia: anaesthetic problems Stiff painful joints and functional disability Uterine and cervicalwall thickening leading to problems at delivery Postpartum acceleration of scleroderma Postpartum difficultieshandling the baby

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year, and the overall cumulative survival rate after 7 years of follow-up was 35% (Medsger and Masi, 1973). Risk factors in these studies were older ages, male sex and black race; pregnancy was not a noted factor. Renal involvement is thought to occur in up to 50% of patients with SSc. The figure depends on the type of study, i.e. ante-mortem or post-mortem, and the intensity of the investigations. It is uncommon when SSc is first diagnosed but usually occurs relatively early in the course of the disease. The average interval between diagnosis of SSc and the onset of renal disease is 3.2 years and the winter seems a very vulnerable time. The presentation may take several forms. One group are those who present with proteinuria and azotaemia (Beigelman et al, 1953; Heptinstall, 1983). These patients appear to follow a chronic course with a prolonged survival time. A second group have well-controlled hypertension or are normotensive and present with rapidly progressive renal failure (Couser et al, 1983); a third group present with the sudden onset of malignant hypertension, sometimes with microangiopathic haemolytic anaemia (Cannon et al, 1974; Couser et al, 1983). Renal function deteriorates rapidly. Prior to the introduction of ACE inhibitors these last two groups did very badly and died within a few months (Smith et al, 1984; Thurm and Alexander, 1984; Beckett et al, 1985). The prominent renal lesion is a vascular one. It is usually restricted to vessels 150-500 wm in diameter and is not always associated with hypertension. However, hypertension occurs in 30% of patients with SSc, and in 7-10% it is malignant. Histologically, the inter|obular arteries show intimal thickening with deposition of a mucinous or finely collagenous material and concentric proliferation of intimal cells. The problem is that these changes may resemble those seen in acute tubular necrosis, haemolytic-uraemic syndrome, idiopathic postpartum renal failure and malignant hypertension. In idiopathic hypertensive patients, vascular changes are usually more pronounced and are often associated with fibrinoid necrosis involving the arteries, together with thrombosis and infarction. When this happens it becomes difficult to differentiate the lesions of SSc from those of other types of malignant hypertension. Glomerular changes consist of slightly increased cellularity of the mesangium and localized irregular thickening of the basement membrane and are nonspecific. A widespread vasculopathy is a characteristic feature of SSc, although its pathogenesis is uncertain. In those patients who do not develop acute renal disease, but who have low grade renal change, it may be a slow process. This would be supported by two findings. Firstly, the presence of renal lesions in post-mortem studies of patients suffering from SSc but who died of nonrenal complications (D'Angelo et al, 1969) and studies in the 1950s showed that, although less than 10% of the patients studied had a reduction in glomerular filtration rate, 80% had a reduction in renal plasma flow, suggesting that the pathological changes were longstanding. Presumably the precipitation of acute renal disease indicates the intervention of some new, sudden event or events, which change the course of the disease. Various factors such as pregnancy, hormones, corticosteroid therapy, and coldinduced vasospasm have been considered, but their role in this accelerated

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crisis is, as yet, poorly defined. Renal disease can appear at any stage of the pregnancy and usually presents as hypertension. The differential diagnosis must include renal scleroderma (perhaps previously not clinically apparent), primary renal disease, idiopathic hypertension or accelerated hypertension of the non-toxaemic variety appearing early in the postpartum period. This may masquerade as pre-eclamptic toxaemia and is usually refractory to all kinds of therapy. The postpartum period must be watched very carefully in an SSc patient as it can be a particularly vulnerable time, something perhaps not previously recognized. In all but the most typical case of pre-eclampsia or eclampsia, renal scteroderma should be given a prominent place in the differential diagnosis. This is important because the therapy and prognosis are different from those of pre-eclampsia. It is also possible that the patient may have two of the above conditions, for example toxaemia and renal scleroderma. In most of the reported cases there is no history of renal disease. Only one of the 23 cases reported in Table 3 had a previous history and was on antihypertensive therapy at the onset of the pregnancy. Twenty-two of the patients were normotensive at the onset of the pregnancy. Eleven patients developed hypertension during the pregnancy and one immediately afterwards. Eight of the ten patients with toxaemia had biopsy-proven renal scleroderma. Five or possibly seven of the nine deaths in the series were due to renal disease. Pregnancy in established renal scleroderma should be avoided. If a pregnancy occurs, termination should be offered and, if the pregnancy continues, monitoring must be meticulous and a sustained fall in renal function should lead to consideration of therapeutic termination. Anaesthesia in scleroderma poses yet another potential problem (Thompson and Conklin, 1983; Roelofse and Shipton, 1985; Younker and Harrison, 1985). Anaesthetic agents, both general and dental, have been causally related to the induction of SSc or the progression into scleroderma from primary Raynaud's (personal observation; Black and Welsh 1988b); therefore, anaesthetic agents should be used with caution in such patients. There are practical problems which face the anaesthetist. The thickened skin plus the vasoconstriction frequently makes venous access difficult and venous cut down or central venous catheterization may be necessary. Flexion contractures, again combined with vasoconstriction, may interfere with normal blood pressure readings and pressures may need monitoring via arterial catheterization. Catheterization of the smaller peripheral arteries has been associated with spasm and subsequent necrosis; these vessels should therefore be avoided (Eisele, 1981). Scleroderma patients may exhibit prolonged motor and sensory blockade after delivery and therefore, if regional anaesthesia is used, Eisele has suggested that smaller doses than usual are given. The regional anaesthesia also provides peripheral vasodilatation and increased skin perfusions in the lower limbs, which is helpful in relieving Raynaud's phenomenon. Other measures to prevent Raynaud's include warm intravenous solutions, warm delivery rooms, and thermal socks. Visceral involvement may increase the anaesthetic risk to patients with SSc. If a general anaesthetic is needed, microstomia can make intubation difficult or impossible, nasal or oral

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telangiectasiae can bleed if traumatized, and oesophageal dysmotility and sphincter incompetence can lead to aspiration. Pulmonary hypertension, albeit an infrequent finding, may occur rapidly and pulmonary fibrosis is common. Cardiac function may be compromised because of conduction defects, pericarditis, and heart failure, and renal disease decreases renal perfusion and is accompanied by systemic hypertension. If there are such problems, it may be desirable to insert a pulmonary artery catheter. With such monitoring the haemodynamic effect of both volume shifts and anaesthetic agents can be rapidly assessed and the efficacy of therapy determined. The problems outlined above are common to any patient with scleroderma. The type of anaesthetic and obstetric delivery will obviously be a very individual decision but the preanaesthetic screen must be very comprehensive.

DRUG THERAPY, SCLERODERMA AND PREGNANCY

There is no satisfactory therapy for SSc. Those patients with diffuse progressive systemic disease may be on antifibrotic and/or immunosuppressive therapy such as D-penicillamine, tx-interferon, cyclophosphamide and steroids (Medsger, 1989). Patients with the milder forms of the disease will hopefully be on minimal therapy, which may include vasodilators and/or anti-inflammatory drugs. It is to be hoped that the diffuse group wilt not get pregnant and that the latter, if pregnant, will be managed with no therapy or simple analgesics, paracetamol being the drug of choice. Any analgesic or non-steroidal anti-inflammatory drug (NSAID) prescribed should be one known to be innocuous to the fetus (ibuprofen, ketoprofen and naproxen) and should be used on an intermittent basis at the lowest possible dose. Steroids should not be used unless there is a severe myositis or the patient is in the rampant early inflammatory phase of the disease. All cytotoxic drugs and D-penicillamine should be discontinued. It is interesting to note that recently there has been a report of a successful pregnancy in which a patient with severe disease conceived whilst on nifedipene and captopril and was on these two drugs for most of the pregnancy with no ill effects (Baethge and Wolf, 1989). PREGNANCY AND SCLERODERMA

There is unfortunately no reliable prospective statistical information regarding the incidence or outcome for either the mother or the fetus. Although over 100 cases can be found within the literature, many contain only minimal documentation and the individual cases reported do not represent the general scleroderma population. The larger series of cases are all retrospective (Johnson et al, 1964; Slate and Graham, 1969; Weiner et al, 1986; C. M. Black and S. Lupoli, unpublished data) but at least the most recent ones are case-controlled (Giordano et al, 1985; Silman and Black, 1988; Steen et al, 1989; H. Englert, personal communication). It would

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appear from the available literature that SSc may adversely affect the fetus and the mother but, at present, no accurate prediction is possible and prospective controlled data is sorely needed.

CASE REPORTS

The first reported case appeared in 1932 (Anselmino and Hoffman, 1932). Since then there have been many single case reports which allow only for individual observations (Table 3). In the 23 case reports outlined in Table 3, the age of the patients ranged from 18 to 40 years, although most were less than 30 years old. The disease duration was usually less than 5 years, although it ranged from a few months to 10 years. Nineteen had the diffuse type of scleroderma and four had the limited form. There were nine deaths, eight of these occurring, as would be anticipated, in patients with diffuse disease, and one in a patient who, although having only mild limited disease, developed renal failure in the third trimester. Unfortunately, the variable course of the disease with its exacerbations and remissions and the lack of knowledge concerning pathogenesis makes it difficult to predict accurately the effect of a superimposed pregnancy on the disease. In the 23 cases reported, the disease appears unchanged in ten, progressed in 12, regressed in two, remitted during and progressed after the pregnancy in one, progressed during and remitted after the pregnancy in two, developed during the pregnancy in one, and was not recorded in one. Eleven patients developed toxaemia, five of whom died of renal failure, with biopsy-proven renal scleroderma. There were four other deaths, two from pneumonia, one from sepsis, gastrointestinal haemorrhage and pulmonary hypertension, and one from an unknown cause, although the patient had established renal disease. It is equally difficult from the single case reports to assess the effect of the disease on pregnancy. There were 23 patients and 29 pregnancies. It is not possible to report on prematurity in these pregnancies because of the sporadic and insufficient information available, nor can useful conclusions be drawn concerning fertility. There were two abortions, five perinatal deaths (one intrauterine death undelivered, one stillborn, and three early neonatal deaths). Of the three neonatal deaths, one was due to prematurity at 28 weeks (Spellacy, 1964) and two to multiple congenital abnormalities (Winkelmann, 1965). In one of these cases the mother had been taking chlorambucil until the 10th week of pregnancy. Twenty of the 23 liveborn infants survived. SERIES REPORTS

Reviewing the three reported series (Johnson et al, 1964; Weiner et al, 1986; Slate and Graham, 1968) and our own experience (C. M. Black and S. Lupoli, unpublished data), there were 103 pregnancies. There are some interesting comparisons with and differences from the single case reports.

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Disease duration and ages are similar, i.e. disease duration in both ranged between 2 months and 8 years, and age between 20 and 40 years. The type of disease was, however, different. Most of the patients in the single case reports had diffuse disease, whereas the majority in the large series were limited. Examining the 103 pregnancies, the disease developed during pregnancy in nine, progressed in 32, remitted in 11 and was stable in 35. Information is not available on the remaining 17 (Table 4). These figures appear to compare favourably with the single case reports. In addition, the patients recorded in the larger series had fewer obstetric complications: there were 24 spontaneous abortions, five perinatal deaths (three stillborn, two neonatal deaths), six cases of toxaemia and two maternal deaths. This is hardly surprising as the single cases were presumably selected for their interest, severity and complications. This special selection of patients and lack of control data makes accurate comparison impossible. CASE-CONTROLLED STUDIES There were three reports in the late-1980s and a fourth one is in preparation (Giordano et al, 1985; Silman and Black, 1988; Steen et al, 1989; H. Englert, personal communication). Italian study The first case-controlled study came from Naples (Giordano et al, 1985) and showed an increased incidence of spontaneous abortion in women with SSc versus healthy controls. Of 86 SSc patients, 80 became pregnant. There was a total of 299 pregnancies and 50 of these (28 women) ended in spontaneous abortion. Of the 86 control women, 82 became pregnant and had 332 pregnancies between them, 32 of which terminated in spontaneous abortion. The percentage of abortion in SSc was found to be significantly higher than that of controls (• = 6.36; P < 0.05). The abortions were not in a few habitual aborters. There was no statistical difference in the rate of abortion between the diffuse and limited forms of scleroderma. This study also refutes the previous suggestion (BaUou et al, 1984) that pregnancy is uncommon in SSc. Only six of the 86 patients did not get pregnant. There was, however, a lower number of pregnancies (299) in scleroderma as compared to controls (n = 332). These differences did not reach statistical significance. This paper did not address the question of whether the rate was higher before disease onset. British studies There have been two recent retrospective case-controlled studies from the British group (Silman and Black, 1988; H. Englert, personal communication). The first study showed that women destined to develop scleroderma have an increased rate of infertility and an increased incidence of spontaneous abortions. The results from 155 case-controlled pairs studied showed that women with SSc had three times the rate of spontaneous

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abortion (relative risk 2 : 1) and three times the rate of fertility problems (relative risk 3 : 0; no successful pregnancy by the age of 35) of the control women (Table 5). Multiple abortions were also m o r e frequent in the w o m e n with SSc (Figure 1). A second controlled study yet to be published (H. Englert, personal communication) has analysed the (pre-disease onset) pregnancy history of 625 women. There were three groups in the study population: a case group of 204 w o m e n who had developed scleroderma, and two control groups consisting of 189 community controls and 233 women who developed R a y n a u d ' s p h e n o m e n o n . When compared with the community controls, the scleroderma group showed a significantly greater risk of experiencing a delay in conceiving, being sick during pregnancy, giving birth to an underweight child or experiencing a stillbirth or early neonatal death. With regards to the Raynaud's controls there appeared to be a significantly greater risk in the case group of an underweight child, a stillbirth or early neonatal death. These two studies suggest for the first time that the adverse reproductive history may antedate the clinical diagnosis of SSc by m a n y years and raise the question of whether pregnancy may have an aetiological role. As recorded earlier in this chapter, one hypothesis is that scleroderma represents a type of chronic graft-versus-host disease, and the disease has been reported after Table 5. Concordance in scleroderma: control pairs for spontaneous abortion and other fertility problems. Ever had spontaneous abortion?

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Control{Y;s Relative risk = 2.1 95% Confidence interval 1.0-1.3

Yes No 8 12 25 70 Number of pairs

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Yes No 0 3 9 103 Number of pairs

Ever had spontaneous abortion or fertility problem, or both?

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Relative risk = 2.3 95% Confidence interval 1.2-1.3 From Silman and Black (1988) with permission.

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Figure 1. Number of miscarriagesin women with scleroderma. From Silman and Black (1988) with permission. bone marrow transplantation. In pregnancy, a transplacental transfer of cells between mother and fetus could lead to a state of microchimaerism, and activation of such cells could cause a chronic graft-versus-host type of disease (S. Pereira, personal communication). Whether such a p h e n o m e n o n could occur after blighted pregnancies is unknown. The data from this study provide one explanation of the, as yet unexplained, marked female excess in incidence of this disease, with the peak age of onset occurring shortly after the reproductive period. It is of interest that in the environmentally induced scleroderma which occurred as a chronic sequela of the Spanish rape-seed oil syndrome there was an equal sex incidence in childhood but an eightfold female excess in adult life (A. Arnaiz-Villena, personal communication). Such an observation is consistent with the disease risk being related to both a known environmental agent and a postpubertal factor in women. We hypothesize that the latter factor may be particularly important in some women.

American study A recent large retrospective case-controlled study by Steen and colleagues (1989) was designed to determine the frequency of maternal morbidity, miscarriages, prematurity and fetal death by studying pregnancy outcome in scleroderma patients, neighbourhood controls and patients with chronic rheumatoid arthritis. Two hundred and twenty-three case-controlled patients formed the basis of their study. Their results showed no statistical increase in the rate of miscarriages, fetal death, maternal morbidity or

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mortality. The study did, however, show an increased risk of prematurity and intrauterine growth retardation. Because in those SSc pregnancies with adverse outcomes birth occurred a mean of 3.7 years (range 0.5-11 years) before disease onset, they considered there to be no difference in the proportion or distribution of adverse outcomes based on the timing of the pregnancy in relation to the start of the disease. Caution should be applied in interpreting these results in this way because it may not require an adverse outcome and it may take a longer time than was observed for this chronic disease to express itself. The problem of fertility was not addressed in this study. The current information available from single cases, larger series, and case-controlled studies is interesting and helps provide guidelines for both patients and doctors, but above all it points to the need for careful, longterm prospective studies on these patients. ADVISING PATIENTS WITH SCLERODERMA

The current recommendations to a scleroderma patient who wishes to become pregnant are based on the retrospective information in the literature and our own experience. Ideally, the patient should be advised before embarking on a pregnancy and the advice should represent the combined view of both a physician and an obstetrician who have a special interest in and experience of the field. Although pregnancy is possible, it may be less likely than in the normal population (Silman and Black, 1988; H. Englert, personal communication) and the abortion rate is considered by some to be increased (Slate and Graham, 1968; Giordano et al, 1985; Silman and Black, 1988); the last authors also found that multiple abortions were more frequent in the scleroderma group. However, the recent study from America (Steen et al, 1989) did not confirm these findings. The baby's health is a critical question and patients are always anxious to know if the baby might develop SSc. They can be reassured on this point; the number of multicase families in the world is probably no more than 50 and the genetic susceptibility described (Briggs et al, 1990) is not, in isolation, a sufficient stimulus to produce the disease. There are only three reports in the world literature describing areas of sclerosis in the newborn (Anselmino and Hoffman, 1932; Etterich and Mall, 1955; Ohtaki et al, 1986). Two of these cases may have represented sclerema neonatorum (Winkelmann, 1965) and the third was considered to be neonatal lupus erythematosus and multiple morphoea. The lupus lesions faded and the sclerosed lesions remained static. The pregnancy may adversely affect the underlying disease, but precise prediction and advice is difficult. It would appear from our own experience that those with diffuse disease tend to fare worse and that the deterioration may take some time, perhaps up to several years, to express itself. However, it should also be noted that those with limited disease may develop lifethreatening complications. In the recent case-controlled study in Pittsburgh (Steen et al, 1989) there was no significant deterioration in disease-related

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symptoms after the pregnancy but the authors' interpretation of their results on this point must be treated with care. When prospective mothers are counselled they must be told that there are no absolute prognosticators. It would appear, looking at the available evidence (see Tables 3 and 4), that the extent of diffuse skin disease and systemic involvement, particularly lung, cardiac and renal involvement, may be more important than the length of the disease, and that limited, mild disease carries a better prognosis. Patients should also be made aware of the effect that the enlarging uterus can have on abdominal or chest skin and internal organs. Abdominal sclerosis is rare but chest involvement is more frequent. Other irritating symptoms may be an increase in reflux, oesophagitis and constipation, and the possibility of malabsorption due to small bowel involvement. The third trimester is the most dangerous period, with the risks of sudden hypertension and renal failure and of the necessity of interrupting the pregnancy should one of the vital organs become compromised. Although many case reports highlight these dangers, the recent study by Steen et al (1989) reported that maternal complications were neither more frequent nor more serious in SSc patients than in controls. Specifically, there was no increased frequency of pre-eclampsia/eclampsia or hypertension in scleroderma pregnancies. As mentioned earlier, the postpartum period can be particularly difficult and the patient should be monitored carefully. M A N A G E M E N T OF P R E G N A N C Y

The following are guidelines for management based on the literature and on personal preference. Antenatal care

1. 2.

3. 4.

A complete evaluation should be made as early in the pregnancy as possible. If there is evidence of rapidly extending skin sclerosis, renal disease, pulmonary hypertension, or pulmonary or cardiac disease, termination of pregnancy should be offered. In the absence of these features, the patient should be informed that there is always the possibility of the development of such complications and that they cannot be predicted or their outcome assured. With this information the patient may request termination of pregnancy. If the pregnancy proceeds, antenatal examinations should ideally be fortnightly until the third trimester, and weekly thereafter. Serial antenatal observations should include: (a) Attention to weight, oesophageal and intestinal symptoms, nutritional status and skin care. (b) A full cardiopulmonary examination, with careful checks for peripheral oedema. (c) Monitoring of blood pressure for early detection of hypertension and assessment of its severity.

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(d) Careful assessment of renal function, urine examination and, if indicated, 24-h clearance and creatinine. Musculoskeletal problems and dietary problems should be treated symptomatically.

Labour The delivery should take place where there is easy access to acute medical services. A general anaesthetic may be complicated if the mother has oral or oesophageal involvement. W o m e n with impaired renal function or pulmonary hypertension are most at risk. Postnatal management The postnatal period should be monitored very carefully as acute hypertension with renal and cardiac failure may occur.

CONCLUSIONS Experience of the care and m a n a g e m e n t of pregnancy in patients with systemic sclerosis is still limited, confusing and controversial. Dogmatic advice is impossible. H o w e v e r , there appears to be general agreement that: 1.

2.

Systemic sclerosis may adversely affect pregnancy, although the incidence of such interactions cannot be fully ascertained from the multiple anecdotal reports, uncontrolled series, and limited retrospective case-controlled data available for review. Pregnancy may adversely affect the course of systemic sclerosis, renal disease being a particularly high, and possibly lethal, risk. Again, insufficient data are available.

The information derived from the literature and our own experience suggests that there is a complex interaction between SSc and pregnancy. This relationship is not yet well defined and research is urgently needed to explore femaleness, hormonal status and the development of this unc o m m o n but important connective tissue disorder.

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