9 Pregnancy in the patient with rheumatic disease: the obstetrician's perspective D O N A L D J. D U D L E Y D. W A R E B R A N C H
Pregnancies complicated by maternal rheumatic disease pose unique management problems for the obstetrician and rheumatologist. Aside from their rheumatic disease, these women are predisposed to several significant obstetric complications, including recurrent pregnancy loss, pre-eclampsia, small-for-gestational age pregnancy, fetal distress and prematurity. Therefore, the optimal management of pregnancy in women with rheumatic disease requires close cooperation between the rheumatologist and obstetrician. The purpose of this review is to update the rheumatologist with these obstetric issues and how they affect obstetric management. C O M M O N OBSTETRIC P R O B L E M S IN PATIENTS WITH R H E U M A T I C DISEASE Recurrent pregnancy loss
Recurrent pregnancy loss, or habitual abortion, is defined as repetitive first or second trimester loss. Although somewhat arbitrary, the traditional definition of habitual abortion is three or more consecutive pregnancy losses. For the woman with autoimmune disease, a history of live births does not necessarily eliminate the risk of developing recurrent pregnancy loss. This is also true if she develops her rheumatic disease subsequent to her successful pregnancies. Pregnancy loss has been associated with systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease and rheumatoid arthritis. The most convincing data come from studies in patients with SLE. Recent prospective studies of lupus pregnancies show loss rates of up to 30% (Lockshin et al, 1984; Mintz et al, 1986), and it has been shown that the best predictor of pregnancy loss in patients with SLE (and possibly other autoimmune diseases) is the presence of antiphospholipid antibodies (aPL) (Lockshin et al, 1987). These antibodies can be found in 10-40% of women with SLE (Harris et al, 1985b), but aPL are not found exclusively in patients with SLE and, from the obstetrical perspective, the patient with significant Baillibre' s Clinical Rheumatology--
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titres of aPL in the absence of SLE poses a clinical problem. Patients with aPL measured as a circulating lupus anticoagulant (LA), a biologically false positive test for syphilis (VDRL), anticardiolipin antibodies (aCL), and certain clinical findings are now considered to constitute a unique syndrome, the antiphospholipid syndrome (APS) (Harris, 1987). The serological and clinical diagnosis of the antiphospholipid syndrome is described in detail by Harris in Chapter 4. APS patients with pregnancy loss have a disproportionate number of second trimester fetal deaths (Branch and Scott, 1990). These account for about 30-45% of pregnancy losses in patients with antiphospholipid syndrome (Branch and Scott, 1990). Other causes of recurrent pregnancy loss usually result in first trimester losses. Second trimester fetal death is a distinctly rare event in the general population. The cause of fetal death in women with APS appears to be vasculopathy and thrombosis in the maternal decidual arterioles supporting the pregnancy. A wide variety of mechanisms have been suggested to explain how aPL might cause decidual vasculopathy and thrombosis. Inhibition of prostacyclin, with subsequent vasoconstriction and platelet aggregation, has been suggested by Carreras et al (1981), but we and other investigators have not been able to reproduce these findings (Dudley et al, 1990). Other suggested mechanisms of thrombosis include inhibition of protein C activation (Cariou et al, 1986) and amplification of platelet aggregation (Harris et al, 1985a). We recently reported that purified IgG fractions from patients with APS induce spontaneous abortion after injection into pregnant mice (Branch et al, 1990), Pathological evaluation of the murine placental implantation sites revealed marked fibrin deposition. This is consistent with findings seen in human decidua, and this model may provide useful information in determining the best therapy for this condition. Autoantibodies other than aPL have been implicated in pregnancy loss. Women with a positive antinuclear antibody titre, but no other signs or symptoms of SLE, have been reported to have an increased risk of pregnancy loss (Cowchock et al, 1984). However, a recent prospective controlled study found no difference in the incidence of low titres of antinuclear antibody in non-pregnant women, pregnant women and women with recurrent pregnancy loss (Harger et al, 1989). Since the pathophysiology of autoantibodies in fetal death remains unclear, it may be that the presence of these autoantibodies is merely as markers for abnormal maternal immunological function. This may reflect aberrant immune responses to the conceptus, resulting in fetal destruction. Until the pathophysiology of fetal loss in autoimmunity is determined, therapy aimed at improving pregnancy outcome remains somewhat empirical.
Pre-eclampsia Pre-eclampsia is a multi-organ disease, and in its most severe form results in marked hypertension and dysfunction of the renal, central nervous, hepatic, coagulation, and fetoplacental systems. Pre-eclampsia, as defined by hyper-
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tension, oedema, and proteinuria, occurs in 6-10% of all pregnancies. Women predisposed to pre-eclampsia are nulliparous, young and of lower socioeconomic status. Multiparas of advanced maternal age (> 35 years) are also predisposed to developing the disease. Of great interest is the association of pre-eclampsia with certain rheumatic diseases: 30-50% of women with SLE develop pre-eclampsia (Lockshin et al, 1987). The patients at greatest risk are those with a history of nephropathy. Our clinical impression is that these patients are particularly prone to developing severe pre-eclampsia. In the absence of underlying renal disease, other rheumatic diseases (e.g. rheumatoid arthritis and scleroderma) have not been associated with preeclampsia. However, patients with renal complications of any autoimmune disease are at increased risk. The precise cause and pathophysiology of pre-eclampsia remains elusive. Certainly a prominent feature of this multi-organ disease is enhanced vascular reactivity, possibly due to diffuse damage to the vascular endothelium (Roberts et al, 1989). Plasma fibronectin levels are markedly elevated in women with pre-eclampsia, reflecting diffuse endothelial damage (Stubbs et al, 1984). This may explain why diseases such as SLE, where diffuse endothelial damage secondary to vasculitis is common, are associated with pre-eclampsia. An in-depth examination of a possible immune aetiology of pre-eclampsia follows below. Small-for-gestational-age infants Impaired fetal growth, resulting in a small-for-gestational-age (SGA) infant, occurs more commonly in women with SLE and APS than in normal women (Branch et al, 1985; Mintz et al, 1986). Up to 25% of infants born to women with SLE are SGA. The impaired fetal growth seen in these conditions reflects 'placental insufficiency'. This results from decidual vascular disease limiting blood flow to the placenta. Pre-eclampsia is also associated with SGA fetuses, so it is not surprising that women with certain rheumatic diseases should be at increased risk for SGA. Long-term sequelae in SGA infants includes impaired postnatal growth (although many of these infants eventually weigh the same as matched controls of normal birth weight) and developmental delay (Fancourt et al, 1976; Westwood et al, 1983). Fetal distress The occurrence of pre-eclampsia and impaired fetal growth in association with rheumatic diseases implies a compromised fetal condition. One would anticipate a propensity for fetal distress, as indicated by abnormal antepartum and intrapartum fetal surveillance. This is indeed the case, particularly for the lupus pregnancy complicated with aPL. Lockshin et al (1985a) noted a high correlation between significant titres of aPL and fetal distress in a series of lupus pregnancies. Nine of 21 patients with SLE had fetal distress and all had significant titres of aPL. However, lupus pregnancies are at risk for fetal distress and death even in the absence of aPL. All lupus pregnancies and pregnant women with APS should be followed with a regimen of fetal surveillance (see below).
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Prematurity
Perhaps the most important perinatal health problem in contemporary Western society is prematurity. Prematurity accounts for a disproportionate share of perinatal mortality, morbidity and health care funds. While pregnancies in women with rheumatic diseases probably contribute very little to the overall problem of prematurity, up to 30% of lupus pregnancies are delivered prematurely. The majority of patients with aPL deliver prematurely (Branch and Scott, 1990). In general, the problems mentioned above, i.e. pre-eclampsia, SGA and fetal distress, dictate that premature delivery is required for maternal and fetal well-being. Idiopathic premature labour does not appear to be more of a problem in women with rheumatic disease. Preventing pre-eclampsia and placental insufficiency in women with rheumatic disease can improve perinatal outcome and contribute to fewer premature births.
PRE-ECLAMPSIA: AN IMMUNE DISORDER?
It has long been suggested that pre-eclampsia may primarily be an immunological disorder. First proposed at the turn of the century, this hypothesis received considerable attention in the mid- to late-1970s. Little progress concerning a possible immunological causation of pre-eclampsia has been made; however, the results of recent studies should rekindle interest in a possible immunogenetic aetiology of pre-eclampsia. Several features of pre-eclampsia suggest an immunological aetiology. Some authors emphasize that the preponderance of pre-eclampsia in primigravid patients is evidence for an immune aetiology (Beer, 1978; Beer and Need, 1985), with the relatively lower incidence of the disease in multiparas resulting from some sort of immune tolerance or 'protective immunity'. A related hypothesis holds that the 'adaptive protection' in multiparas is afforded by maternal antibodies that 'block' or mask the maternal immune response to paternal antigens exhibited by the fetus. These so-called blocking antibodies are found predominantly in multiparas and are identified by their ability to suppress the in vitro proliferation of maternal lymphocytes in response to irradiated paternal lymphocytes (Scott et al, 1987). They are virtually never detected in the sera of nulliparous women. Blocking antibodies may function by: (1) binding to paternal antigens on trophoblasts thereby masking recognition by maternal immune effector cells; or (2) reacting with other maternal antibodies (anti-idiotypes) or immune recognition sites on maternal effector cells. Blocking antibodies can be induced by paternal leukocyte transfusions, a treatment used for some cases of unexplained pregnancy loss (Mowbray et al, 1985). It is interesting that there appear to be few, if any, cases of severe pre-eclampsia among women who have received this treatment (Beer and Need, 1985). Blood transfusion also induces the formation of blocking antibodies, and the incidence of preeclampsia likewise appears to be diminished in women who have received transfusions (Feeney et al, 1977).
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There is some evidence that peripheral blood lymphocyte function is altered in women with pre-eclampsia. Utilizing mixed lymphocyte cultures, Redman et al (1982) suggest that there is an inhibitor of maternal lymphocyte response in the sera of women who have pre-eclampsia. Pre-eclampsia is also characterized by impaired function of maternal T lymphocytes (Birkeland and Kristofferson, 1979). This has been attributed in part to changes in the percentages of different subsets of T cells in the peripheral blood. Some studies report an increase in the helper (CD4+) T cell population (Moore et al, 1983), while other studies have found no difference in the proportion of T cell subsets (Sridama et al, 1983). Natural killer cell activity has also been reported to be impaired by sera from pre-eclamptic women (Alanen and Lassila, 1982). These studies on peripheral blood suggest that there is immune 'hyporesponsiveness' in women with preeclampsia. Certain histopathological findings also suggest that pre-eclampsia may have an immune aetiology. Endotheliosis is the characteristic pathological change found in the renal glomeruli of women with pre-eclampsia (Spargo et al, 1976). Sub-endothelial deposits characteristic of endotheliosis appear to be mesangial and endothelial cells containing phagocytosed fibrin, fibrin degradation products and immunoglobulins. These deposits may be due to immune complex deposition, although definitive proof of this is lacking. Histological changes in the placental bed, so-called 'fibrinoid necrosis' (the deposition of fibrin beneath cytotrophoblast), also suggest an ongoing immune process. The incidence and severity of fibrinoid necrosis of chorionic villi appears to be greater in women with pre-eclampsia (Kitzmiller, 1977). Indeed, diseases associated with increased placental mass theoretically provide a greater antigenic stimulus and are associated with a greater incidence of pre-eclampsia. This 'hyperplacentosis' is noted in women with molar disease, multiple gestation and fetal hydrops, all conditions associated with a higher than expected incidence of pre-eclampsia (Scott, 1958; McFarlane and Scott, 1976). Also cited as supporting evidence of an immune aetiology is the rapid clearance of the disease after delivery of the placenta, the alleged antigenic stimulus (Beer, 1978). In addition to the possible role of placental fetopaternal antigens, some investigators have suggested that paternal antigens present in seminal fluid may have a role in the genesis of pre-eclampsia. Klonoff-Cohen et al (1989) recently reported that women who use barrier contraceptives and who became pregnant with few exposures to paternal semen have a significantly higher risk for developing pre-eclampsia. They found a 2.37-fold increased risk of pre-eclampsia in women who used barrier contraceptives as compared to women who used oral contraceptives or no contraception. The authors suggested that women who use barrier contraceptive methods may contribute to 60% of episodes of pre-eclampsia. Stratification of the study populations according to the number of semen exposures revealed that women with greater exposure had a lower relative risk of developing preeclampsia. Their findings are compatible with those of Need (1975), who found that women who change sexual partners and then become pregnant seem to have the same risk for pre-eclampsia as do women with their first
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pregnancy. They also reported an increased risk for pre-eclampsia in women who have pregnancies by anonymous donor insemination (Need et al, 1983). These reports suggest that repeated exposure to paternal seminal antigens 'immunize' the prospective mother, thereby reducing the 'rejection' of the fetus, as manifest by pre-eclampsia. The evidence supporting an immune aetiology for pre-eclampsia is tenuous at best. The 'protective effect' of a first pregnancy is contrary to a basic tenet of cellular immunology, i.e. memory. One would expect that a rejection response to the fetus in the first pregnancy would result in subsequent pregnancies having the same response mediated by amnestic memory, yet there is no evidence that this occurs. It also seems surprising that a primarily immune disorder should clear within hours after removal of the placenta. Most cellular immune responses (e.g. delayed-type hypersensitivity) require several days for complete resolution. Other evidence for an immune aetiology of pre-eclampsia can be criticized. Given the multi-organ dysfunction characteristic of pre-eclampsia, it is not surprising to find that cellular immune function and lymphocyte populations may be altered. These changes may be an effect, rather than a cause, of the disease. Additionally, no other immunological diseases, except perhaps thrombocytopenic thrombotic purpura or haemolytic-uraemic syndrome (if one considers these immune diseases), present with symptoms resembling pre-eclampsia. Although the data concerning exposure to paternal seminal antigens support an immune aetiology, physiological evidence for the role of paternal antigens in the aetiology of pre-eclampsia is lacking. These epidemiological studies rely heavily on patient history, and recall bias may hinder making solid conclusions. There is no immunological or biochemical evidence for semen or sperm-mediated alterations of maternal immune responsiveness that would result in the subsequent development of preeclampsia. C O U R S E OF R H E U M A T I C DISEASE DURING P R E G N A N C Y
Although older retrospective studies implied that SLE is often exacerbated by pregnancy, prospective studies suggest that pregnant women with SLE are not at increased risk for flares of disease (Lockshin et al, 1984; Mintz et al, 1986). The best work is that of Lockshin and co-workers. Their initial case control study (1984) indicated that the course of SLE in pregnant patients was similar to that in matched non-pregnant controls. A recent update of their series (Lockshin, 1989) found that the risk for clinically important exacerbation during pregnancy is 1 in every 8.9 pregnancies. This risk appeared to be independent of corticosteroid treatment. In another carefully followed but uncontrolled population (Varner et al, 1983), SLE flares were found to be associated with decreases in immunosuppressive therapy. Women with APS are a different group of patients. One expression of their disease, i.e. fetal death, can only occur during pregnancy. Pregnancy is a relatively thrombogenic state and patients with APS appear to be at
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substantial risk for arterial and venous thromboembolic disease. In our series of women with antiphospholipid antibodies, 28% had a thrombotic episode and over half of these episodes occurred during pregnancY or while on oral contraceptives (Branch and Scott, 1990). Of interest, a rare patient will have detectable aPL only during pregnancy. Rheumatoid arthritis appears to ameliorate with pregnancy, although this is somewhat variable. In fact, about one-quarter of rheumatoid arthritis patients remain unchanged or worsen during pregnancy (Cecere and Persellin, 1981). Improvement, when it occurs, typically is apparent by the end of the first trimester. Postpartum relapse is exceedingly common (Persellin, 1977). Limited information is available concerning scleroderma, mixed connective tissue disease and dermatomyositis/polymyositisduring pregnancy, and one cannot draw firm conclusions about the course of these diseases during pregnancy. The data that are available have been reviewed extensively recently (Zurier, 1989). The course of disease in polyarteritis nodosa, however, deserves special mention. Of eleven cases of polyarteritis nodosa associated with pregnancy reported through 1989, all seven women developing polyarteritis nodosa during pregnancy or the immediate postpartum period died (Klipple and Riordan, 1989). Most deaths were attributable to renal failure or severe hypertension. In women who are in clinical remission prior to becoming pregnant, maternal outcome appears to be somewhat better. Pregnancy termination or spontaneous abortion does not necessarily insure maternal survival (Klipple and Riordan, 1989). OBSTETRIC MANAGEMENT
Specific medical therapy Medical therapy for pregnant women with rheumatic disease is prescribed for three reasons: (1) treatment of active rheumatic disease, (2) prevention of pregnancy loss, and (3) prevention of pre-eclampsia.
Rheumatic disease activity The management of disease activity in pregnant patients with rheumatic diseases is discussed at length in Chapter 10. It is important, however, to make special mention of pregnant patients with SLE as controlling disease activity has been shown to be one of the most important factors determining fetal outcome (Mintz and Rodriguez-Alvarez, 1989). The mainstay of therapy for pregnant patients with active lupus is corticosteroids and while teratological studies of corticosteroids have shown that laboratory animals have an increased incidence of cleft palate (Fainstat, 1954), a wealth of clinical experience with human pregnancies has shown that teratogenic defects are not increased in human neonates born of mothers taking corticosteroids. In fact, the placenta has an abundance of 11-[3-ol dehydrogenase, which converts prednisolone to the inactive ll-keto form
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(Levitz et al, 1978). Corticosteroids less well metabolized by the placenta, e.g. betamethasone and dexamethasone, have been associated with derangement of organ growth in primates and should not be administered chronically during pregnancy (Johnson et al, 1979). The reader is referred to Chapter 10 for a detailed discussion of the use of non-steroidal anti-inflammatory drugs (including aspirin), antimalarial drugs and cytotoxic immunosuppressive drugs (including azathioprine and cyclophosphamide) in pregnant patients with rheumatic diseases.
Prevention of pregnancy loss Other medical therapy is aimed at preventing pregnancy loss in women with APS, with or without SLE. Although the best treatment regimen is controversial, a combination of low-dose aspirin (< 80 mg/day) and subcutaneous heparin or corticosteroids has been reported to improve the liveborn rate to better than 60% (Lubbe et al, 1983; Branch and Scott, 1990; Rosove et al, 1990). Lubbe et al (1983) initially showed that five of six women with lupus anticoagulant had successful pregnancy outcomes when treated with high doses of prednisone (at least 40 mg/day) and low-dose aspirin (75 mg/day). Using similar treatment regimens, successful pregnancy outcomes have been reported by several other groups (Branch et al, 1985; Lockwood et al, 1986; Derkson et al, 1988; Englert et al, 1988; Hahn et al, 1988). Although favourable, our own experience is somewhat less optimistic than that of Lubbe. We have treated 39 pregnancies in women with APS with prednisone and low-dose aspirin. While 70% of pregnancies have resulted in the delivery of a viable infant, many of these pregnancies were complicated by severe pre-eclampsia and required preterm delivery (Branch et al, 1985; Kochenour et al, 1987). Fetal deaths occurred in seven pregnancies and spontaneous abortions occurred in six pregnancies. Our experience suggests that treatment with corticosteroids and low-dose aspirin is beneficial but does not guarantee success. While not as successful as Lubbe, our results are more encouraging than those recently reported by Lockshin and colleagues (1989). In their report, only two of 11 (18%) women with fetal loss delivered live infants when treated with prednisone and only seven of 21 (33%) had live infants regardless of therapy. The side-effects associated with high-dose steroid therapy, coupled with the finding that thrombosis is a key feature of women with APL, has led some to use heparin therapy during pregnancy (Gardlund, 1984; Rosove et al, 1990). The recent case series reported by Rosove et al (1990) documents successful outcomes in 14 of 15 pregnancies treated with heparin. Our experience with the regimen of subcutaneous heparin and low-dose aspirin is limited to eight cases. All delivered viable infants, but two were delivered early for pre-eclampsia and fetal distress. Because the data suggest an equal benefit of heparin and low-dose aspirin compared with aspirin and prednisone, and the known side-effects of steroid therapy, we generally start our patients on subcutaneous heparin and low-dose aspirin once pregnancy is recognized.
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Five women on whom we consulted were treated with a combination of prednisone, heparin and low-dose aspirin. Although all pregnancies resulted in live births, one of the women suffered vertebral compression fractures during treatment. This is a recognized complication of the osteopenic effect of prednisone and heparin therapy. Because of the serious nature and potential neurological risk of these fractures, we believe that the combination of prednisone and heparin should be avoided unless they are clearly shown to be superior to other treatments. Another potentially useful treatment for aPL-associated pregnancy loss is high dose intravenous immunoglobulin (IVIg). We and other investigators have had favourable outcomes using IVIg (Scott et al, 1988; Carreras et al, 1988; Parke et al, 1989; WF Lubbe, personal communication). The lack of serious adverse effects makes this expensive therapy somewhat attractive. However, we now have accumulated experience with three cases treated with IVIg (in combination with prednisone and low-dose aspirin) and the results are not so encouraging. Two of the treated pregnancies ended in late first trimester fetal deaths. Since IVIg was used because of previous treatment failures, these women may represent particularly difficult cases. Our current treatment regimen is implemented as follows. Patients with APS who are attempting conception are encouraged to take low-dose aspirin (after a normal platelet count is confirmed). When the patient becomes pregnant, we obtain an ultrasound at 5-6 weeks to determine the presence or absence of a fetus. When a viable fetus is identified, we begin subcutaneous heparin at 15 000 units/day. The dose is increased to 20 000 units/day at the beginning of the second trimester and continued until delivery approaches. At our institution, the heparin dosage is not adjusted based on coagulation testing (virtually all of the patients have circulating lupus anticoagulant); nor do we have assays for heparin levels available. Rosove et al (1990) used the activated partial thromboplastin time or thrombin time to monitor patients with APS on heparin. The mean daily dose of heparin in their series was 24 700 units, not significantly different from the daily dosage we recommend. We do not use heparin in pregnant women already on moderate-to-high doses of corticosteroids for control of autoimmune disease; we simply add low-dose aspirin.
Prevention of pre-eclampsia Recent studies indicate that low-dose aspirin may prevent the development of pre-eclampsia in selected patients (Wallenburg et al, 1986; Benigni et al, 1989; Schiff et al, 1989), perhaps by restoring or maintaining an appropriate balance of maternal vascular prostacyclin and thromboxane A (Schiff et al, 1989). Low-dose aspirin acts mainly to inhibit thromboxane A production by activated platelets, and does not appear to have the adverse fetal effects seen at higher doses (Sibai et al, 1989). Additionally, low-dose aspirin has few significant maternal side-effects and is generally well tolerated. We therefore treat all patients with SLE with low-dose aspirin because they are at relatively high risk of developing pre-eclampsia (Lockshin et al, 1987).
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Prenatal care and laboratory evaluation
At the first obstetric visit of patients with an autoimmune disorder, we obtain a complete blood count (including platelets), renal function tests (including 24-hour urine collection for protein and creatinine clearance), and other routine prenatal screening tests, including serological screening for syphilis ( V D R L ) . A false-positive V D R L may be a m a r k e r for w o m e n at risk for recurrent miscarriage (Thornton et al, 1987), although a recent large study found that w o m e n with a false positive V D R L experienced no increased risk of fetal death when compared with w o m e n with a negative V D R L (Koskela et al, 1988). Also, a false positive V D R L is a m a r k e r for aPL, but we routinely obtain blood for aPL (LA and anticardiolipin antibodies) regardless of the results of the V D R L . We also r e c o m m e n d obtaining anti-SSA and anti-SSB antibody titres since these are associated with neonatal lupus erythematosus syndrome (NLES) and complete congenital heart block ( C C H B ) (Scott et al, 1983). We recognize that the risk for N L E S is low; however, high titres of anti-SSA or anti-SSB alerts the patient and physician to the possibility of C C H B . The m e a s u r e m e n t of other autoantibodies or their titres does not alter obstetric management. We do not periodically measure aPL levels or coagulation times in patients with antiphospholipid antibodies, even if they are being treated for APS (see above). As long as the patient remains asymptomatic, we generally do not obtain serial serum c o m p l e m e n t levels or assays for circulating immune complexes, as these determinations may not predict impending autoimmune or obstetric problems (Lockshin et al, 1985b) although others have found low complem e n t levels to be a m a r k e r for disease activity and useful in differentiating SLE disease activity from pre-eclampsia (Buyon et al, 1986). It has been suggested that one of the best indicators of SLE activity is frequent assessm e n t of the patient's symptoms (Varner et al, 1983). Therefore pregnant Table 1. Laboratory tests helpful in distinguishing SLE from preeclampsia. Clinical finding Haematological indices Thrombocytopenia (< 100 000 ix1-1) Haemolytic anaemia Coomb's positive Microangiopathic Leukopenia Serological parameters Elevated hepatic function tests Elevated creatinine Diminished antithrombin III Hypocomplementaemia Urinary parameters Red cell casts Haematuria
SLE
Pre-eclampsia
+
+++
++ +++
++ -
+ ++ + +++
+++ + ++ +
+++ +++
+
+, Indicates the degree of helpfulness in diagnosing each disorder.
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patients with rheumatic diseases should have more frequent prenatal visits than normal pregnant patients. We see them at least every 2 weeks in the first two trimesters and weekly in the third trimester. In the past, we have advocated obtaining haematological and renal function parameters at least once per trimester, but we are no longer convinced that this information is helpful in managing asymptomatic patients. Currently, we allow the patient's signs and symptoms to dictate laboratory testing. A particularly difficult clinical problem in patients with SLE is distinguishing between lupus nephritis and pre-eclampsia. Each may present with proteinuria, hypertension and evidence of multi-organ dysfunction. Laboratory features that may be helpful are displayed in Table 1, but the final diagnosis may ultimately require renal biopsy. The role of ultrasonography All pregnant rheumatic patients should have an obstetric sonographic evaluation at 16-20 weeks gestation. This not only serves to confirm gestational age but also establishes baseline parameters for subsequent evaluation of fetal growth. Patients with a history of mid-trimester fetal distress or death may require earlier studies. After the initial sonogram, repeat evaluations should be done approximately every 4 weeks to assess the fetal growth and amniotic fluid volume status. Impaired fetal growth and diminished amniotic fluid volume (oligohydramnios) may suggest placental insufficiency. If there is evidence of impaired fetal growth or oligohydramnios, more frequent ultrasonic evaluations and fetal surveillance testing is necessary. Fetal surveillance: practice and interpretation The goal of antepartum fetal surveillance is to identify the fetus at risk for hypoxic damage or death due to placental insufficiency. There are a variety of methods to assess the fetus, including fetal heart rate monitoring (nonstress testing, NST, contraction stress test, CST) and sonographic evaluation (biophysical profile, BPP; Doppler velocimetry). The NST, CST and BPP assess a spectrum of fetal biophysical behaviour. The NST and CST are based on interpretations of the fetal heart rate, as recorded by a Doppler cardiotocograph, in response to fetal movement (NST) or mild uterine contractions (CST). The BPP sonographically evaluates different aspects of fetal activity, and Doppler velocimetry indirectly measures the degree of resistance in the placental and fetal circulation. In brief, a normal 'reactive' NST is characterized by two fetal heart rate accelerations (15 beats/rain for 15 s occurring within 20 rain) in response to fetal movement. The absence of fetal heart rate accelerations (a 'nonreactive' NST) suggests fetal hypoxia with acidosis. Other abnormalities of the fetal heart rate that suggest hypoxia include fetal tachycardia, the loss of heart rate variability, and spontaneous heart rate decelerations. The CST, considered by many to be the 'gold standard' of fetal surveillance, requires the induction of mild uterine contractions (at least three in 10min). A normal 'negative' CST is marked by the absence of fetal heart rate
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decelerations in response to the contractions. Conversely, the hypoxaemic fetus demonstrates heart rate decelerations associated with the contractions (a 'positive' CST). The BPP combines the NST with ultrasonographic assessment of four fetal characteristics. These include determinations of amniotic fluid volume, fetal breathing movements, fetal tone (flexion and extension) and fetal movement. For each of the five parameters, a score of 2 indicates a normal result and a score of 0 indicates an abnormal result. If all features of the BPP are normal, then a score of 10 is given. A score of 6 or less is considered evidence of fetal compromise. Because the NST and amniotic fluid volume appear to be the best predictors of fetal well-being or compromise, many practitioners assess only these two parameters for fetal surveillance. Doppler flow studies of the umbilical artery have been reported to be a helpful adjunct in the antepartum evaluation of the fetus at risk for compromise (Trudinger and Giles, 1989). Elevations of the systolic to diastolic ratio of blood flow velocity in the umbilical artery indicates increased placental resistance secondary to hypoxaemia. Complete absence of diastolic flow appears to be a particularly worrisome indicator of fetal hypoxaemia. This finding, in association with impaired fetal growth and/or oligohydramnios, is an indication for delivery. A recent report by Trudinger et al (1988) suggests that Doppler velocimetry may be particularly useful in the management of pregnancies complicated by aPL. They followed six women with significant levels of aPL using a variety of fetal surveillance techniques. In three of the six cases, the Doppler results suggested fetal hypoxaemia before other surveillance tests. However, we have managed over 50 pregnancies complicated by aPL without the use of Doppler velocimetry and no patient has suffered a fetal death after reaching fetal viability. Thus, we feel that Doppler velocimetry is no better than other methods of fetal surveillance. While the best method of fetal surveillance is controversial, we initially use the NST because it is relatively inexpensive and sensitive. In pregnant patients with rheumatic disease, we combine the NST with amniotic fluid volume assessment. These tests are started between 28 and 32 weeks gestation, depending upon the clinical situation, and are repeated weekly as long as the pregnancy proceeds normally. A non-reactive NST associated with severe oligohydramnios is an indication for immediate delivery. However, a non-reactive NST in conjunction with normal amniotic fluid volume requires confirmatory testing to determine the need for delivery. We generally use the CST for confirmation because of its proven track record. If subsequent testing also suggests fetal hypoxaemia, then delivery is mandated. Regarding fetal surveillance, several important clinical points deserve emphasis: .
Patients with a history of mid-trimester fetal compromise or death should have fetal surveillance started as soon as the obstetrician and patient are willing to intervene with delivery for fetal compromise (between 23 and 28 weeks gestation, depending upon the regional experience). For example, Druzin et al (1987) reported abnormal fetal
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3.
4.
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heart rate tracings in the second trimester in women with APS. These were associated with severe fetal compromise or death, and the authors recommend intervening for these abnormalities if the pregnancy has advanced to the point of neonatal survival. False positive NSTs are relatively common (greater than 50%), particularly at gestational ages under 30 weeks (Thacker and Berkelman, 1985). Therefore, abnormal NSTs must be evaluated by subsequent testing (CST or BPP). The gestational age is one of the most important variables in deciding how to manage abnormal fetal surveillance testing. At or beyond 36 weeks gestation, abnormal or suspicious surveillance can be managed by delivery without fear of substantial neonatal complications due to prematurity. The decision to intervene for fetal compromise is dependent upon the interpretation of the fetal surveillance testing and requires sound medical judgement.
Delivery and postpartum management Even if all goes well, it is prudent to deliver patients with SLE or APS at 36-40 weeks gestation. Patients with (1) normal blood pressure, (2) normal fetal surveillance, and (3) stable rheumatic disease may be allowed to enter spontaneous labour. Patients with fetal compromise or hypertension may have to be delivered prematurely by induction of labour or caesarean section, depending upon the clinical situation. Neither SLE or APS is an indication for proceeding directly to caesarean section if the fetus is deemed capable of tolerating labour. Patients who have been on glucocorticosteroids within the past year should receive 'stress doses' of steroids during labour or at the time of caesarean section. All women, even those without underlying medical problems, are at an increased risk for venous thrombosis in the postpartum period. Because those with APS represent a high-risk population, we treat them with prophylactic heparin (5000-7500 units subcutaneously twice a day) for 3-6 weeks after delivery (Kochenour et al, 1987). We do not believe that exacerbation of autoimmune disease is particularly likely, therefore, we do not routinely treat patients with immunosuppressive agents after delivery (the so-called 'burst-and-taper' treatment). As in the antepartum period, we feel that the most important aspect of postpartum care is close medical surveillance for evidence of autoimmune disease activity. SUMMARY Patients with rheumatic diseases who become pregnant are justifiably categorized as having high-risk pregnancies. Utilizing a multidisciplinary approach, including perinatologists, rheumatologists and anaesthetists, successful pregnancies have become the rule rather than the exception. However, women with rheumatic disease are particularly prone to develop
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s e r i o u s o b s t e t r i c p r o b l e m s w h i c h o f t e n r e s u l t in e a r l y h o s p i t a l i z a t i o n a n d delivery. Although vigilant obstetric care improves perinatal outcome, p r e m a t u r i t y will c o n t i n u e t o b e a m a j o r p r o b l e m c o m p l i c a t i n g p r e g n a n c i e s in w o m e n w i t h r h e u m a t i c d i s e a s e .
REFERENCES Alanen A & Lassila O (1982) Deficient natural killer cell function in preeclampsia. Obstetrics and Gynecology 60: 631-634. Beer AE (1978) Possible immunologic bases of preeclampsiaJeclampsia. Seminars in Perinatology 2: 39-59. Beer AE & Need JA (1985) Immunological aspects of preeclampsia/eclampsia. Birth Defects: Original Article Series 21: 131-154. Benigni A, Gregorini G, Frusca T et al (1989) Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. New England Journal of Medicine 321: 357-362. Birkeland SA & Kristofferson K (1979) Pre-eclampsia--a state of mother-fetus imbalance. Lancet ii: 720--723. Branch DW & Scott JR (1990) Clinical implications of antiphospholipid antibodies: the Utah experience. In Harris EN (ed.) Phospholipid-Binding Antibodies (in press). Boca Raton, FA: CRC Press. Branch DW, Scott JR, Kochenour NK et al (1985) Obstetric complications associated with the lupus anticoagulant. New England Journal of Medicine 313: 1322-1326. Branch DW, Dudley D J, Mitchell MD et al (1990) IgG fractions from patients with antiphospholipid antibodies cause fetal death in Balb/c mice: a model for autoimmune fetal loss. American Journal of Obstetrics and Gynecology 163: 210-216. Buyon JP et al (1986) Serum complement values (C3 and C4) to differentiate between systemic lupus activity and pre-eclampsia. American Journal of Medicine 81: 194--200. Cariou R, Tobelem B, Soria C et al (1986) Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. New England Journal of Medicine 314: 1193-1194. Carreras LO, Vermylen J, Spitz B e t al (1981) 'Lupus' anticoagulant and inhibition of prostacyclin formation in patients with repeated abortion, intrauterine growth retardation and intrauterine death. British Journal of Obstetrics and Gynaecology 88: 890-894. Carreras LO, Perez GN, Vega HR et al (1988) Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet ii: 393-394. Cecere FA & Persellin RH (1981) The interaction of pregnancy and the rheumatic diseases. Clinics in Rheumatic Diseases 7: 747-768. Cowchock S, Dehoratius RD, Wapner RJ & Jackson LG (1984) Subclinical autoimmune disease and unexplained abortion'~ American Journal of Obstetrics and Gynecology 150: 367-371. Derkson RHWM, Brunise HW, Christiaens CrCML et al (1988) A controlled clinical trial on the efficacy of medicamentous treatment of pregnant patients with antiphospholipid antibodies--a preliminary report. Clinical and Experimental Rheumatology 6: 202. Druzin ML, Lockshin MD, Edersheim TG et al (1987) Second-trimester fetal monitoring and preterm delivery in pregnancies with systemic lupus erythematosus and/or circulating anticoagulant. American Journal of Obstetrics and Gynecology 157: 1503-1510. Dudley D J, Mitchell MD & Branch DW (1990) Pathophysiology of antiphospholipid antibodies: absence of prostaglandin-mediated effects on cultured endothelium. American Journal of Obstetrics and Gynecology 162: 953-959. Englert HJ, Derue GM, Loizou S et al (1988) Pregnancy and lupus: prognostic indicators and response to treatment. Quarterly Journal of Medicine 66: 125-136. Estes D & Larson D (1965) Systemic lupus erythematosus and pregnancy. Clinics in Obstetrics and Gynecology 8: 307-321. Fainstat T (1954) Cortisone-induced congenital cleft palate in rabbits. Endocrinology 55: 502. Fancourt R, Campbell S, Harvey D et al (1976) Follow-up studies of small-for-dates babies. British Medical Journal 1: 1435-1437.
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Feeney JG, Tovey LAC & Scott JS (1977) Influence of previous blood transfusion on the incidence of pre-eclampsia. Lancet i: 874-875. Gardlund B (1984) The lupus inhibitor in thromboembolic disease and intrauterine death in the absence of systemic lupus. Acta Medicina Scandinavia 215: 293-298. Hahn L, Norberg A, 8tigendal Let al (1988) The antiphospholipid antibody syndrome and pregnancy outcome--Swedish experiences. Clinical and Experimental Rheumatology 6: 204. Harger JH, Rabin BS & Marchese SG (1989) The prognostic value of antinuclear antibodies in women with recurrent pregnancy losses: a prospective controlled study. Obstetrics and Gynecology 73: 41%424. Harris EN (1987) Syndrome of the black swan. British Journal of Rheumatology 26: 324-326. Harris EN, Asherson RA, Gharavi AE et al (1985a) Thromboeytopenia in SLE and related disorders: association with antieardiolipin antibodies. British Journal of Haematology 59: 227-230. Harris EN, Gharavi A E & Hughes GRV (1985b) Antiphospholipid antibodies. Clinics in Rheumatic Diseases 11: 591-609. Johnson JWC, Mitzner W, London WT, Palmer AE & Scott R (1979) Betamethasone and the rhesus fetus: multisystem effects. American Journal of Obstetrics and Gynecology 133: 67%684. Kitzmiller JL (1977) Immunologic approaches to the study of preeclampsia. Clinical Obstetrics and Gynaecology 20: 717-735. Klipple GL & Riordan KK (1989) Rare inflammatory and hereditary connective tissue diseases. Rheumatic Disease Clinics of North America 15: 383-398. Klonoff-Cohen HS, Savitz DA, Cefalo RC & McCann MF (1989) An epidemiologic study of contraception and preeclampsia. Journal of the American Medical Association 262: 31433147. Kochenour NK, Branch DW, Rote NS et al (1987) A new postpartum syndrome associated with antiphospholipid antibodies. Obstetrics and Gynecology 69: 460--468. Koskela P, Vaarala O, Makitalo R et al (1988) Significance of false positive syphilis reactions and anticardiolipin antibodies in a nationwide series of pregnant women. Journal of Rheumatology 15: 70-73. Levitz M, Jansen V & Dancis J (1978) The transfer and metabolism of corticosteroids in the perfused human placenta. American Journal of Obstetrics and Gynecology 132: 363. Lockshin MD (1989) Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis and Rheumatism 32: 665-670. Lockshin MD, Reinitz E, Druzin ML et al (1984) Lupus pregnancy. Case control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. American Journal of Medicine 77: 893-898. Lockshin MD, Druzin ML, Goei Set al (1985a) Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. New England Journal of Medicine 313: 152-156. Lockshin MD, Harpel PC, Druzin ML et al (1985b) Lupus pregnancy II. Unusual pattern of hypocomplementemia and thrombocytopenia in the pregnant patient. Arthritis and Rheumatism 28: 58-66. Lockshin MD, Qamar T & Druzin ML (1987) Hazards of lupus pregnancy. Journal of Rheumatology 14(supplement 13): 214-217. Lockshin MD, Druzin ML & Qamar T (1989) Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. American Journal of Obstetrics and Gynecology 160: 43%443. Lockwood CJ, Reece EZ, Romero R et al (1986) Antiphospholipid antibody and pregnancy wastage. Lancet ii: 742-743. Lubbe WF, Butler WS, Palmer SJ & Liggins GC (1983) Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet i: 1361-1363. McFarlane A & Scott JS (1976) Pre-eclampsia/eclampsia in twin pregnancies. Journal of Medical Genetics 13: 108-121. Mintz G & Rodriquez-Alvarez E (1989) Systemic lupus erythematosus. Rheumatic Disease Clinics of North America 15: 255-274. Mintz G, Niz J, Gutierrez G e t al (1986) Prospective study of pregnancy in systemic lupus erythematosus: results of a multidisciplinary approach. Journal of Rheumatology 13: 732-739.
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Moore MP, Carter NP & Redman CWG (1983) Lymphocyte subsets in normal and preeclamptic pregnancies. British Journal of Obstetrics and Gynaecology 90: 326-331. Mowbray JF, Liddell H, Underwood JL et al (1985) Controlled trial of treatment of recurrent spontaneous abortion by immunization with paternal cells. Lancet i: 941-943. Need JA (1975) Pre-eclampsia in pregnancies by different fathers: immunological studies. British Medical Journal 1: 548-549. Need JA, Bell B, Meffin E & Jones WR (1983) Pre-eclampsia in pregnancies from donor inseminations. Journal of Reproductive Immunology 5: 329-338. Parke AL, Maier D, Wilson D, Andreoli J & Ballow M (1989) Intravenous gamma globulin, antiphospholipid antibodies and pregnancy. Annals oflnternal Medicine 110: 495-496. Persellin RH (1977) The effect of pregnancy on rheumatoid arthritis. Bulletin of the Rheumatic Diseases 27: 922-927. Redrnan CWG, Sargent IL & Stirrat GM (1982) Maternal cell-mediated immunity in normal and preeclamptic pregnancy. Clinical and Experimental Immunology 50: 601-609. Roberts JM, Taylor RN, Musci TJ et al (1989) Preeclampsia: an endothelial cell disorder. American Journal of Obstetrics and Gynecology 161: 12013-1204. Rosove MH, Tabsh K, Wasserstrum N et al (1990) Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstetricsand Gynecology 75: 630-634. Schiff E, Peleg E, Goldenberg M et al (1989) The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. New England Journal of Medicine 321: 351-356. Scott JS, Maddison PJ, Taylor PV et al (1983) Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. New EnglandJournalofMedicine309: 209-212. Scott JR, Rote NS & Branch DW (1987) Immunologic aspects of recurrent abortion and fetal death. Obstetrics and Gynecology 70: 645-656. Scott JR, Branch DW, Kochenour NK et al (1988) Intravenous globulin treatment of pregnant patients with recurrent pregnancy loss due to antiphospholipid antibodies and Rh isoimmunization. American Journal of Obstetrics and Gynecology 159: 1055-1056. Scott JS (1958) Pregnancy toxemia associated with hydrops fetalis, hydatiform mole and hydramnios. Journal of Obstetrics and Gynaecology of the British Commonwealth 65: 689-700. Sibai BM, Mirro R, Chesney CM & Leffler C (1989) Low-dose aspirin in pregnancy. Obstetrics and Gynecology 74: 551-557. Spargo B, Lichtig C, Luger AM et al (1976) The renal lesion in pre-eclampsia. Perspectives in Nephrology and Hypertension 5: 129-137. Sridama V, Yang S, Moawad A & DeGroot LJ (1983) T-cell subsets in patients with preeclampsia. American Journal of Obstetrics and Gynecology 147: 566-569. Stubbs TM, Lazarchik J & Horger EO (1984) Plasma fibronectin levels in pre-eclampsia: a possible biochemical marker for vascular endothelial damage. American Journal of Obstetrics and Gynecology 150: 885--887. Thacker SB & Berkelman RL (1985) Assessing the diagnostic accuracy and efficacy of selected antepartum surveillance techniques. Obstetrical and Gynecological Survey 41: 121-141. Thornton JG, Foote GA, Page GE et al (1987) False positive results of tests for syphilis and outcome of pregnancy: a retrospective case-control study. British Medical Journal 295: 355-356. Trudinger BJ & Giles WB (1989) Clinical and pathologic correlations of umbilical and uterine artery waveforms. Clinical Obstetrics and Gynaecology 32: 669-678. Trudinger BJ, Stewart GJ, Cook CM, Connelly A & Exner T (1988) Monitoring lupus anticoagulant-positive pregnancies with umbilical artery flow velocity waveforms. Obstetrics and Gynecology 72: 215-218. Varner MW, Meehan RT, Syrop CH et al (1983) Pregnancy in patients with systemic lupus erythematosus. American Journal of Obstetrics and Gynecology 145" 1025-1040. Wallenburg HCS, Makovitz JW, Dekker GA et al (1986) Low-dose aspirin prevents pregnancyinduced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet i: 1-3. Westwood M, Kramer MS, Munz D et al (1983) Growth and development of full-term nonasphyxiated small-for-gestational-age newborns: follow-up through adolescence. Pediatrics 71: 376-382. Zurier R (1989) Pregnancy in patients with rheumatic diseases. Rheumatic Disease Clinics of North America 15: 2.
Pregnancies complicated by maternal rheumatic disease pose unique management problems for the obstetrician and rheumatologist. Aside from their rheumatic disease, these women are predisposed to several significant obstetric complications, including recurrent pregnancy loss, pre-eclampsia, small-for-gestational age pregnancy, fetal distress and prematurity. Therefore, the optimal management of pregnancy in women with rheumatic disease requires close cooperation between the rheumatologist and obstetrician. The purpose of this review is to update the rheumatologist with these obstetric issues and how they affect obstetric management. C O M M O N OBSTETRIC P R O B L E M S IN PATIENTS WITH R H E U M A T I C DISEASE Recurrent pregnancy loss
Recurrent pregnancy loss, or habitual abortion, is defined as repetitive first or second trimester loss. Although somewhat arbitrary, the traditional definition of habitual abortion is three or more consecutive pregnancy losses. For the woman with autoimmune disease, a history of live births does not necessarily eliminate the risk of developing recurrent pregnancy loss. This is also true if she develops her rheumatic disease subsequent to her successful pregnancies. Pregnancy loss has been associated with systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease and rheumatoid arthritis. The most convincing data come from studies in patients with SLE. Recent prospective studies of lupus pregnancies show loss rates of up to 30% (Lockshin et al, 1984; Mintz et al, 1986), and it has been shown that the best predictor of pregnancy loss in patients with SLE (and possibly other autoimmune diseases) is the presence of antiphospholipid antibodies (aPL) (Lockshin et al, 1987). These antibodies can be found in 10-40% of women with SLE (Harris et al, 1985b), but aPL are not found exclusively in patients with SLE and, from the obstetrical perspective, the patient with significant Baillibre' s Clinical Rheumatology--
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titres of aPL in the absence of SLE poses a clinical problem. Patients with aPL measured as a circulating lupus anticoagulant (LA), a biologically false positive test for syphilis (VDRL), anticardiolipin antibodies (aCL), and certain clinical findings are now considered to constitute a unique syndrome, the antiphospholipid syndrome (APS) (Harris, 1987). The serological and clinical diagnosis of the antiphospholipid syndrome is described in detail by Harris in Chapter 4. APS patients with pregnancy loss have a disproportionate number of second trimester fetal deaths (Branch and Scott, 1990). These account for about 30-45% of pregnancy losses in patients with antiphospholipid syndrome (Branch and Scott, 1990). Other causes of recurrent pregnancy loss usually result in first trimester losses. Second trimester fetal death is a distinctly rare event in the general population. The cause of fetal death in women with APS appears to be vasculopathy and thrombosis in the maternal decidual arterioles supporting the pregnancy. A wide variety of mechanisms have been suggested to explain how aPL might cause decidual vasculopathy and thrombosis. Inhibition of prostacyclin, with subsequent vasoconstriction and platelet aggregation, has been suggested by Carreras et al (1981), but we and other investigators have not been able to reproduce these findings (Dudley et al, 1990). Other suggested mechanisms of thrombosis include inhibition of protein C activation (Cariou et al, 1986) and amplification of platelet aggregation (Harris et al, 1985a). We recently reported that purified IgG fractions from patients with APS induce spontaneous abortion after injection into pregnant mice (Branch et al, 1990), Pathological evaluation of the murine placental implantation sites revealed marked fibrin deposition. This is consistent with findings seen in human decidua, and this model may provide useful information in determining the best therapy for this condition. Autoantibodies other than aPL have been implicated in pregnancy loss. Women with a positive antinuclear antibody titre, but no other signs or symptoms of SLE, have been reported to have an increased risk of pregnancy loss (Cowchock et al, 1984). However, a recent prospective controlled study found no difference in the incidence of low titres of antinuclear antibody in non-pregnant women, pregnant women and women with recurrent pregnancy loss (Harger et al, 1989). Since the pathophysiology of autoantibodies in fetal death remains unclear, it may be that the presence of these autoantibodies is merely as markers for abnormal maternal immunological function. This may reflect aberrant immune responses to the conceptus, resulting in fetal destruction. Until the pathophysiology of fetal loss in autoimmunity is determined, therapy aimed at improving pregnancy outcome remains somewhat empirical.
Pre-eclampsia Pre-eclampsia is a multi-organ disease, and in its most severe form results in marked hypertension and dysfunction of the renal, central nervous, hepatic, coagulation, and fetoplacental systems. Pre-eclampsia, as defined by hyper-
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tension, oedema, and proteinuria, occurs in 6-10% of all pregnancies. Women predisposed to pre-eclampsia are nulliparous, young and of lower socioeconomic status. Multiparas of advanced maternal age (> 35 years) are also predisposed to developing the disease. Of great interest is the association of pre-eclampsia with certain rheumatic diseases: 30-50% of women with SLE develop pre-eclampsia (Lockshin et al, 1987). The patients at greatest risk are those with a history of nephropathy. Our clinical impression is that these patients are particularly prone to developing severe pre-eclampsia. In the absence of underlying renal disease, other rheumatic diseases (e.g. rheumatoid arthritis and scleroderma) have not been associated with preeclampsia. However, patients with renal complications of any autoimmune disease are at increased risk. The precise cause and pathophysiology of pre-eclampsia remains elusive. Certainly a prominent feature of this multi-organ disease is enhanced vascular reactivity, possibly due to diffuse damage to the vascular endothelium (Roberts et al, 1989). Plasma fibronectin levels are markedly elevated in women with pre-eclampsia, reflecting diffuse endothelial damage (Stubbs et al, 1984). This may explain why diseases such as SLE, where diffuse endothelial damage secondary to vasculitis is common, are associated with pre-eclampsia. An in-depth examination of a possible immune aetiology of pre-eclampsia follows below. Small-for-gestational-age infants Impaired fetal growth, resulting in a small-for-gestational-age (SGA) infant, occurs more commonly in women with SLE and APS than in normal women (Branch et al, 1985; Mintz et al, 1986). Up to 25% of infants born to women with SLE are SGA. The impaired fetal growth seen in these conditions reflects 'placental insufficiency'. This results from decidual vascular disease limiting blood flow to the placenta. Pre-eclampsia is also associated with SGA fetuses, so it is not surprising that women with certain rheumatic diseases should be at increased risk for SGA. Long-term sequelae in SGA infants includes impaired postnatal growth (although many of these infants eventually weigh the same as matched controls of normal birth weight) and developmental delay (Fancourt et al, 1976; Westwood et al, 1983). Fetal distress The occurrence of pre-eclampsia and impaired fetal growth in association with rheumatic diseases implies a compromised fetal condition. One would anticipate a propensity for fetal distress, as indicated by abnormal antepartum and intrapartum fetal surveillance. This is indeed the case, particularly for the lupus pregnancy complicated with aPL. Lockshin et al (1985a) noted a high correlation between significant titres of aPL and fetal distress in a series of lupus pregnancies. Nine of 21 patients with SLE had fetal distress and all had significant titres of aPL. However, lupus pregnancies are at risk for fetal distress and death even in the absence of aPL. All lupus pregnancies and pregnant women with APS should be followed with a regimen of fetal surveillance (see below).
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Prematurity
Perhaps the most important perinatal health problem in contemporary Western society is prematurity. Prematurity accounts for a disproportionate share of perinatal mortality, morbidity and health care funds. While pregnancies in women with rheumatic diseases probably contribute very little to the overall problem of prematurity, up to 30% of lupus pregnancies are delivered prematurely. The majority of patients with aPL deliver prematurely (Branch and Scott, 1990). In general, the problems mentioned above, i.e. pre-eclampsia, SGA and fetal distress, dictate that premature delivery is required for maternal and fetal well-being. Idiopathic premature labour does not appear to be more of a problem in women with rheumatic disease. Preventing pre-eclampsia and placental insufficiency in women with rheumatic disease can improve perinatal outcome and contribute to fewer premature births.
PRE-ECLAMPSIA: AN IMMUNE DISORDER?
It has long been suggested that pre-eclampsia may primarily be an immunological disorder. First proposed at the turn of the century, this hypothesis received considerable attention in the mid- to late-1970s. Little progress concerning a possible immunological causation of pre-eclampsia has been made; however, the results of recent studies should rekindle interest in a possible immunogenetic aetiology of pre-eclampsia. Several features of pre-eclampsia suggest an immunological aetiology. Some authors emphasize that the preponderance of pre-eclampsia in primigravid patients is evidence for an immune aetiology (Beer, 1978; Beer and Need, 1985), with the relatively lower incidence of the disease in multiparas resulting from some sort of immune tolerance or 'protective immunity'. A related hypothesis holds that the 'adaptive protection' in multiparas is afforded by maternal antibodies that 'block' or mask the maternal immune response to paternal antigens exhibited by the fetus. These so-called blocking antibodies are found predominantly in multiparas and are identified by their ability to suppress the in vitro proliferation of maternal lymphocytes in response to irradiated paternal lymphocytes (Scott et al, 1987). They are virtually never detected in the sera of nulliparous women. Blocking antibodies may function by: (1) binding to paternal antigens on trophoblasts thereby masking recognition by maternal immune effector cells; or (2) reacting with other maternal antibodies (anti-idiotypes) or immune recognition sites on maternal effector cells. Blocking antibodies can be induced by paternal leukocyte transfusions, a treatment used for some cases of unexplained pregnancy loss (Mowbray et al, 1985). It is interesting that there appear to be few, if any, cases of severe pre-eclampsia among women who have received this treatment (Beer and Need, 1985). Blood transfusion also induces the formation of blocking antibodies, and the incidence of preeclampsia likewise appears to be diminished in women who have received transfusions (Feeney et al, 1977).
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There is some evidence that peripheral blood lymphocyte function is altered in women with pre-eclampsia. Utilizing mixed lymphocyte cultures, Redman et al (1982) suggest that there is an inhibitor of maternal lymphocyte response in the sera of women who have pre-eclampsia. Pre-eclampsia is also characterized by impaired function of maternal T lymphocytes (Birkeland and Kristofferson, 1979). This has been attributed in part to changes in the percentages of different subsets of T cells in the peripheral blood. Some studies report an increase in the helper (CD4+) T cell population (Moore et al, 1983), while other studies have found no difference in the proportion of T cell subsets (Sridama et al, 1983). Natural killer cell activity has also been reported to be impaired by sera from pre-eclamptic women (Alanen and Lassila, 1982). These studies on peripheral blood suggest that there is immune 'hyporesponsiveness' in women with preeclampsia. Certain histopathological findings also suggest that pre-eclampsia may have an immune aetiology. Endotheliosis is the characteristic pathological change found in the renal glomeruli of women with pre-eclampsia (Spargo et al, 1976). Sub-endothelial deposits characteristic of endotheliosis appear to be mesangial and endothelial cells containing phagocytosed fibrin, fibrin degradation products and immunoglobulins. These deposits may be due to immune complex deposition, although definitive proof of this is lacking. Histological changes in the placental bed, so-called 'fibrinoid necrosis' (the deposition of fibrin beneath cytotrophoblast), also suggest an ongoing immune process. The incidence and severity of fibrinoid necrosis of chorionic villi appears to be greater in women with pre-eclampsia (Kitzmiller, 1977). Indeed, diseases associated with increased placental mass theoretically provide a greater antigenic stimulus and are associated with a greater incidence of pre-eclampsia. This 'hyperplacentosis' is noted in women with molar disease, multiple gestation and fetal hydrops, all conditions associated with a higher than expected incidence of pre-eclampsia (Scott, 1958; McFarlane and Scott, 1976). Also cited as supporting evidence of an immune aetiology is the rapid clearance of the disease after delivery of the placenta, the alleged antigenic stimulus (Beer, 1978). In addition to the possible role of placental fetopaternal antigens, some investigators have suggested that paternal antigens present in seminal fluid may have a role in the genesis of pre-eclampsia. Klonoff-Cohen et al (1989) recently reported that women who use barrier contraceptives and who became pregnant with few exposures to paternal semen have a significantly higher risk for developing pre-eclampsia. They found a 2.37-fold increased risk of pre-eclampsia in women who used barrier contraceptives as compared to women who used oral contraceptives or no contraception. The authors suggested that women who use barrier contraceptive methods may contribute to 60% of episodes of pre-eclampsia. Stratification of the study populations according to the number of semen exposures revealed that women with greater exposure had a lower relative risk of developing preeclampsia. Their findings are compatible with those of Need (1975), who found that women who change sexual partners and then become pregnant seem to have the same risk for pre-eclampsia as do women with their first
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pregnancy. They also reported an increased risk for pre-eclampsia in women who have pregnancies by anonymous donor insemination (Need et al, 1983). These reports suggest that repeated exposure to paternal seminal antigens 'immunize' the prospective mother, thereby reducing the 'rejection' of the fetus, as manifest by pre-eclampsia. The evidence supporting an immune aetiology for pre-eclampsia is tenuous at best. The 'protective effect' of a first pregnancy is contrary to a basic tenet of cellular immunology, i.e. memory. One would expect that a rejection response to the fetus in the first pregnancy would result in subsequent pregnancies having the same response mediated by amnestic memory, yet there is no evidence that this occurs. It also seems surprising that a primarily immune disorder should clear within hours after removal of the placenta. Most cellular immune responses (e.g. delayed-type hypersensitivity) require several days for complete resolution. Other evidence for an immune aetiology of pre-eclampsia can be criticized. Given the multi-organ dysfunction characteristic of pre-eclampsia, it is not surprising to find that cellular immune function and lymphocyte populations may be altered. These changes may be an effect, rather than a cause, of the disease. Additionally, no other immunological diseases, except perhaps thrombocytopenic thrombotic purpura or haemolytic-uraemic syndrome (if one considers these immune diseases), present with symptoms resembling pre-eclampsia. Although the data concerning exposure to paternal seminal antigens support an immune aetiology, physiological evidence for the role of paternal antigens in the aetiology of pre-eclampsia is lacking. These epidemiological studies rely heavily on patient history, and recall bias may hinder making solid conclusions. There is no immunological or biochemical evidence for semen or sperm-mediated alterations of maternal immune responsiveness that would result in the subsequent development of preeclampsia. C O U R S E OF R H E U M A T I C DISEASE DURING P R E G N A N C Y
Although older retrospective studies implied that SLE is often exacerbated by pregnancy, prospective studies suggest that pregnant women with SLE are not at increased risk for flares of disease (Lockshin et al, 1984; Mintz et al, 1986). The best work is that of Lockshin and co-workers. Their initial case control study (1984) indicated that the course of SLE in pregnant patients was similar to that in matched non-pregnant controls. A recent update of their series (Lockshin, 1989) found that the risk for clinically important exacerbation during pregnancy is 1 in every 8.9 pregnancies. This risk appeared to be independent of corticosteroid treatment. In another carefully followed but uncontrolled population (Varner et al, 1983), SLE flares were found to be associated with decreases in immunosuppressive therapy. Women with APS are a different group of patients. One expression of their disease, i.e. fetal death, can only occur during pregnancy. Pregnancy is a relatively thrombogenic state and patients with APS appear to be at
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substantial risk for arterial and venous thromboembolic disease. In our series of women with antiphospholipid antibodies, 28% had a thrombotic episode and over half of these episodes occurred during pregnancY or while on oral contraceptives (Branch and Scott, 1990). Of interest, a rare patient will have detectable aPL only during pregnancy. Rheumatoid arthritis appears to ameliorate with pregnancy, although this is somewhat variable. In fact, about one-quarter of rheumatoid arthritis patients remain unchanged or worsen during pregnancy (Cecere and Persellin, 1981). Improvement, when it occurs, typically is apparent by the end of the first trimester. Postpartum relapse is exceedingly common (Persellin, 1977). Limited information is available concerning scleroderma, mixed connective tissue disease and dermatomyositis/polymyositisduring pregnancy, and one cannot draw firm conclusions about the course of these diseases during pregnancy. The data that are available have been reviewed extensively recently (Zurier, 1989). The course of disease in polyarteritis nodosa, however, deserves special mention. Of eleven cases of polyarteritis nodosa associated with pregnancy reported through 1989, all seven women developing polyarteritis nodosa during pregnancy or the immediate postpartum period died (Klipple and Riordan, 1989). Most deaths were attributable to renal failure or severe hypertension. In women who are in clinical remission prior to becoming pregnant, maternal outcome appears to be somewhat better. Pregnancy termination or spontaneous abortion does not necessarily insure maternal survival (Klipple and Riordan, 1989). OBSTETRIC MANAGEMENT
Specific medical therapy Medical therapy for pregnant women with rheumatic disease is prescribed for three reasons: (1) treatment of active rheumatic disease, (2) prevention of pregnancy loss, and (3) prevention of pre-eclampsia.
Rheumatic disease activity The management of disease activity in pregnant patients with rheumatic diseases is discussed at length in Chapter 10. It is important, however, to make special mention of pregnant patients with SLE as controlling disease activity has been shown to be one of the most important factors determining fetal outcome (Mintz and Rodriguez-Alvarez, 1989). The mainstay of therapy for pregnant patients with active lupus is corticosteroids and while teratological studies of corticosteroids have shown that laboratory animals have an increased incidence of cleft palate (Fainstat, 1954), a wealth of clinical experience with human pregnancies has shown that teratogenic defects are not increased in human neonates born of mothers taking corticosteroids. In fact, the placenta has an abundance of 11-[3-ol dehydrogenase, which converts prednisolone to the inactive ll-keto form
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(Levitz et al, 1978). Corticosteroids less well metabolized by the placenta, e.g. betamethasone and dexamethasone, have been associated with derangement of organ growth in primates and should not be administered chronically during pregnancy (Johnson et al, 1979). The reader is referred to Chapter 10 for a detailed discussion of the use of non-steroidal anti-inflammatory drugs (including aspirin), antimalarial drugs and cytotoxic immunosuppressive drugs (including azathioprine and cyclophosphamide) in pregnant patients with rheumatic diseases.
Prevention of pregnancy loss Other medical therapy is aimed at preventing pregnancy loss in women with APS, with or without SLE. Although the best treatment regimen is controversial, a combination of low-dose aspirin (< 80 mg/day) and subcutaneous heparin or corticosteroids has been reported to improve the liveborn rate to better than 60% (Lubbe et al, 1983; Branch and Scott, 1990; Rosove et al, 1990). Lubbe et al (1983) initially showed that five of six women with lupus anticoagulant had successful pregnancy outcomes when treated with high doses of prednisone (at least 40 mg/day) and low-dose aspirin (75 mg/day). Using similar treatment regimens, successful pregnancy outcomes have been reported by several other groups (Branch et al, 1985; Lockwood et al, 1986; Derkson et al, 1988; Englert et al, 1988; Hahn et al, 1988). Although favourable, our own experience is somewhat less optimistic than that of Lubbe. We have treated 39 pregnancies in women with APS with prednisone and low-dose aspirin. While 70% of pregnancies have resulted in the delivery of a viable infant, many of these pregnancies were complicated by severe pre-eclampsia and required preterm delivery (Branch et al, 1985; Kochenour et al, 1987). Fetal deaths occurred in seven pregnancies and spontaneous abortions occurred in six pregnancies. Our experience suggests that treatment with corticosteroids and low-dose aspirin is beneficial but does not guarantee success. While not as successful as Lubbe, our results are more encouraging than those recently reported by Lockshin and colleagues (1989). In their report, only two of 11 (18%) women with fetal loss delivered live infants when treated with prednisone and only seven of 21 (33%) had live infants regardless of therapy. The side-effects associated with high-dose steroid therapy, coupled with the finding that thrombosis is a key feature of women with APL, has led some to use heparin therapy during pregnancy (Gardlund, 1984; Rosove et al, 1990). The recent case series reported by Rosove et al (1990) documents successful outcomes in 14 of 15 pregnancies treated with heparin. Our experience with the regimen of subcutaneous heparin and low-dose aspirin is limited to eight cases. All delivered viable infants, but two were delivered early for pre-eclampsia and fetal distress. Because the data suggest an equal benefit of heparin and low-dose aspirin compared with aspirin and prednisone, and the known side-effects of steroid therapy, we generally start our patients on subcutaneous heparin and low-dose aspirin once pregnancy is recognized.
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Five women on whom we consulted were treated with a combination of prednisone, heparin and low-dose aspirin. Although all pregnancies resulted in live births, one of the women suffered vertebral compression fractures during treatment. This is a recognized complication of the osteopenic effect of prednisone and heparin therapy. Because of the serious nature and potential neurological risk of these fractures, we believe that the combination of prednisone and heparin should be avoided unless they are clearly shown to be superior to other treatments. Another potentially useful treatment for aPL-associated pregnancy loss is high dose intravenous immunoglobulin (IVIg). We and other investigators have had favourable outcomes using IVIg (Scott et al, 1988; Carreras et al, 1988; Parke et al, 1989; WF Lubbe, personal communication). The lack of serious adverse effects makes this expensive therapy somewhat attractive. However, we now have accumulated experience with three cases treated with IVIg (in combination with prednisone and low-dose aspirin) and the results are not so encouraging. Two of the treated pregnancies ended in late first trimester fetal deaths. Since IVIg was used because of previous treatment failures, these women may represent particularly difficult cases. Our current treatment regimen is implemented as follows. Patients with APS who are attempting conception are encouraged to take low-dose aspirin (after a normal platelet count is confirmed). When the patient becomes pregnant, we obtain an ultrasound at 5-6 weeks to determine the presence or absence of a fetus. When a viable fetus is identified, we begin subcutaneous heparin at 15 000 units/day. The dose is increased to 20 000 units/day at the beginning of the second trimester and continued until delivery approaches. At our institution, the heparin dosage is not adjusted based on coagulation testing (virtually all of the patients have circulating lupus anticoagulant); nor do we have assays for heparin levels available. Rosove et al (1990) used the activated partial thromboplastin time or thrombin time to monitor patients with APS on heparin. The mean daily dose of heparin in their series was 24 700 units, not significantly different from the daily dosage we recommend. We do not use heparin in pregnant women already on moderate-to-high doses of corticosteroids for control of autoimmune disease; we simply add low-dose aspirin.
Prevention of pre-eclampsia Recent studies indicate that low-dose aspirin may prevent the development of pre-eclampsia in selected patients (Wallenburg et al, 1986; Benigni et al, 1989; Schiff et al, 1989), perhaps by restoring or maintaining an appropriate balance of maternal vascular prostacyclin and thromboxane A (Schiff et al, 1989). Low-dose aspirin acts mainly to inhibit thromboxane A production by activated platelets, and does not appear to have the adverse fetal effects seen at higher doses (Sibai et al, 1989). Additionally, low-dose aspirin has few significant maternal side-effects and is generally well tolerated. We therefore treat all patients with SLE with low-dose aspirin because they are at relatively high risk of developing pre-eclampsia (Lockshin et al, 1987).
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Prenatal care and laboratory evaluation
At the first obstetric visit of patients with an autoimmune disorder, we obtain a complete blood count (including platelets), renal function tests (including 24-hour urine collection for protein and creatinine clearance), and other routine prenatal screening tests, including serological screening for syphilis ( V D R L ) . A false-positive V D R L may be a m a r k e r for w o m e n at risk for recurrent miscarriage (Thornton et al, 1987), although a recent large study found that w o m e n with a false positive V D R L experienced no increased risk of fetal death when compared with w o m e n with a negative V D R L (Koskela et al, 1988). Also, a false positive V D R L is a m a r k e r for aPL, but we routinely obtain blood for aPL (LA and anticardiolipin antibodies) regardless of the results of the V D R L . We also r e c o m m e n d obtaining anti-SSA and anti-SSB antibody titres since these are associated with neonatal lupus erythematosus syndrome (NLES) and complete congenital heart block ( C C H B ) (Scott et al, 1983). We recognize that the risk for N L E S is low; however, high titres of anti-SSA or anti-SSB alerts the patient and physician to the possibility of C C H B . The m e a s u r e m e n t of other autoantibodies or their titres does not alter obstetric management. We do not periodically measure aPL levels or coagulation times in patients with antiphospholipid antibodies, even if they are being treated for APS (see above). As long as the patient remains asymptomatic, we generally do not obtain serial serum c o m p l e m e n t levels or assays for circulating immune complexes, as these determinations may not predict impending autoimmune or obstetric problems (Lockshin et al, 1985b) although others have found low complem e n t levels to be a m a r k e r for disease activity and useful in differentiating SLE disease activity from pre-eclampsia (Buyon et al, 1986). It has been suggested that one of the best indicators of SLE activity is frequent assessm e n t of the patient's symptoms (Varner et al, 1983). Therefore pregnant Table 1. Laboratory tests helpful in distinguishing SLE from preeclampsia. Clinical finding Haematological indices Thrombocytopenia (< 100 000 ix1-1) Haemolytic anaemia Coomb's positive Microangiopathic Leukopenia Serological parameters Elevated hepatic function tests Elevated creatinine Diminished antithrombin III Hypocomplementaemia Urinary parameters Red cell casts Haematuria
SLE
Pre-eclampsia
+
+++
++ +++
++ -
+ ++ + +++
+++ + ++ +
+++ +++
+
+, Indicates the degree of helpfulness in diagnosing each disorder.
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patients with rheumatic diseases should have more frequent prenatal visits than normal pregnant patients. We see them at least every 2 weeks in the first two trimesters and weekly in the third trimester. In the past, we have advocated obtaining haematological and renal function parameters at least once per trimester, but we are no longer convinced that this information is helpful in managing asymptomatic patients. Currently, we allow the patient's signs and symptoms to dictate laboratory testing. A particularly difficult clinical problem in patients with SLE is distinguishing between lupus nephritis and pre-eclampsia. Each may present with proteinuria, hypertension and evidence of multi-organ dysfunction. Laboratory features that may be helpful are displayed in Table 1, but the final diagnosis may ultimately require renal biopsy. The role of ultrasonography All pregnant rheumatic patients should have an obstetric sonographic evaluation at 16-20 weeks gestation. This not only serves to confirm gestational age but also establishes baseline parameters for subsequent evaluation of fetal growth. Patients with a history of mid-trimester fetal distress or death may require earlier studies. After the initial sonogram, repeat evaluations should be done approximately every 4 weeks to assess the fetal growth and amniotic fluid volume status. Impaired fetal growth and diminished amniotic fluid volume (oligohydramnios) may suggest placental insufficiency. If there is evidence of impaired fetal growth or oligohydramnios, more frequent ultrasonic evaluations and fetal surveillance testing is necessary. Fetal surveillance: practice and interpretation The goal of antepartum fetal surveillance is to identify the fetus at risk for hypoxic damage or death due to placental insufficiency. There are a variety of methods to assess the fetus, including fetal heart rate monitoring (nonstress testing, NST, contraction stress test, CST) and sonographic evaluation (biophysical profile, BPP; Doppler velocimetry). The NST, CST and BPP assess a spectrum of fetal biophysical behaviour. The NST and CST are based on interpretations of the fetal heart rate, as recorded by a Doppler cardiotocograph, in response to fetal movement (NST) or mild uterine contractions (CST). The BPP sonographically evaluates different aspects of fetal activity, and Doppler velocimetry indirectly measures the degree of resistance in the placental and fetal circulation. In brief, a normal 'reactive' NST is characterized by two fetal heart rate accelerations (15 beats/rain for 15 s occurring within 20 rain) in response to fetal movement. The absence of fetal heart rate accelerations (a 'nonreactive' NST) suggests fetal hypoxia with acidosis. Other abnormalities of the fetal heart rate that suggest hypoxia include fetal tachycardia, the loss of heart rate variability, and spontaneous heart rate decelerations. The CST, considered by many to be the 'gold standard' of fetal surveillance, requires the induction of mild uterine contractions (at least three in 10min). A normal 'negative' CST is marked by the absence of fetal heart rate
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decelerations in response to the contractions. Conversely, the hypoxaemic fetus demonstrates heart rate decelerations associated with the contractions (a 'positive' CST). The BPP combines the NST with ultrasonographic assessment of four fetal characteristics. These include determinations of amniotic fluid volume, fetal breathing movements, fetal tone (flexion and extension) and fetal movement. For each of the five parameters, a score of 2 indicates a normal result and a score of 0 indicates an abnormal result. If all features of the BPP are normal, then a score of 10 is given. A score of 6 or less is considered evidence of fetal compromise. Because the NST and amniotic fluid volume appear to be the best predictors of fetal well-being or compromise, many practitioners assess only these two parameters for fetal surveillance. Doppler flow studies of the umbilical artery have been reported to be a helpful adjunct in the antepartum evaluation of the fetus at risk for compromise (Trudinger and Giles, 1989). Elevations of the systolic to diastolic ratio of blood flow velocity in the umbilical artery indicates increased placental resistance secondary to hypoxaemia. Complete absence of diastolic flow appears to be a particularly worrisome indicator of fetal hypoxaemia. This finding, in association with impaired fetal growth and/or oligohydramnios, is an indication for delivery. A recent report by Trudinger et al (1988) suggests that Doppler velocimetry may be particularly useful in the management of pregnancies complicated by aPL. They followed six women with significant levels of aPL using a variety of fetal surveillance techniques. In three of the six cases, the Doppler results suggested fetal hypoxaemia before other surveillance tests. However, we have managed over 50 pregnancies complicated by aPL without the use of Doppler velocimetry and no patient has suffered a fetal death after reaching fetal viability. Thus, we feel that Doppler velocimetry is no better than other methods of fetal surveillance. While the best method of fetal surveillance is controversial, we initially use the NST because it is relatively inexpensive and sensitive. In pregnant patients with rheumatic disease, we combine the NST with amniotic fluid volume assessment. These tests are started between 28 and 32 weeks gestation, depending upon the clinical situation, and are repeated weekly as long as the pregnancy proceeds normally. A non-reactive NST associated with severe oligohydramnios is an indication for immediate delivery. However, a non-reactive NST in conjunction with normal amniotic fluid volume requires confirmatory testing to determine the need for delivery. We generally use the CST for confirmation because of its proven track record. If subsequent testing also suggests fetal hypoxaemia, then delivery is mandated. Regarding fetal surveillance, several important clinical points deserve emphasis: .
Patients with a history of mid-trimester fetal compromise or death should have fetal surveillance started as soon as the obstetrician and patient are willing to intervene with delivery for fetal compromise (between 23 and 28 weeks gestation, depending upon the regional experience). For example, Druzin et al (1987) reported abnormal fetal
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3.
4.
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heart rate tracings in the second trimester in women with APS. These were associated with severe fetal compromise or death, and the authors recommend intervening for these abnormalities if the pregnancy has advanced to the point of neonatal survival. False positive NSTs are relatively common (greater than 50%), particularly at gestational ages under 30 weeks (Thacker and Berkelman, 1985). Therefore, abnormal NSTs must be evaluated by subsequent testing (CST or BPP). The gestational age is one of the most important variables in deciding how to manage abnormal fetal surveillance testing. At or beyond 36 weeks gestation, abnormal or suspicious surveillance can be managed by delivery without fear of substantial neonatal complications due to prematurity. The decision to intervene for fetal compromise is dependent upon the interpretation of the fetal surveillance testing and requires sound medical judgement.
Delivery and postpartum management Even if all goes well, it is prudent to deliver patients with SLE or APS at 36-40 weeks gestation. Patients with (1) normal blood pressure, (2) normal fetal surveillance, and (3) stable rheumatic disease may be allowed to enter spontaneous labour. Patients with fetal compromise or hypertension may have to be delivered prematurely by induction of labour or caesarean section, depending upon the clinical situation. Neither SLE or APS is an indication for proceeding directly to caesarean section if the fetus is deemed capable of tolerating labour. Patients who have been on glucocorticosteroids within the past year should receive 'stress doses' of steroids during labour or at the time of caesarean section. All women, even those without underlying medical problems, are at an increased risk for venous thrombosis in the postpartum period. Because those with APS represent a high-risk population, we treat them with prophylactic heparin (5000-7500 units subcutaneously twice a day) for 3-6 weeks after delivery (Kochenour et al, 1987). We do not believe that exacerbation of autoimmune disease is particularly likely, therefore, we do not routinely treat patients with immunosuppressive agents after delivery (the so-called 'burst-and-taper' treatment). As in the antepartum period, we feel that the most important aspect of postpartum care is close medical surveillance for evidence of autoimmune disease activity. SUMMARY Patients with rheumatic diseases who become pregnant are justifiably categorized as having high-risk pregnancies. Utilizing a multidisciplinary approach, including perinatologists, rheumatologists and anaesthetists, successful pregnancies have become the rule rather than the exception. However, women with rheumatic disease are particularly prone to develop
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s e r i o u s o b s t e t r i c p r o b l e m s w h i c h o f t e n r e s u l t in e a r l y h o s p i t a l i z a t i o n a n d delivery. Although vigilant obstetric care improves perinatal outcome, p r e m a t u r i t y will c o n t i n u e t o b e a m a j o r p r o b l e m c o m p l i c a t i n g p r e g n a n c i e s in w o m e n w i t h r h e u m a t i c d i s e a s e .
REFERENCES Alanen A & Lassila O (1982) Deficient natural killer cell function in preeclampsia. Obstetrics and Gynecology 60: 631-634. Beer AE (1978) Possible immunologic bases of preeclampsiaJeclampsia. Seminars in Perinatology 2: 39-59. Beer AE & Need JA (1985) Immunological aspects of preeclampsia/eclampsia. Birth Defects: Original Article Series 21: 131-154. Benigni A, Gregorini G, Frusca T et al (1989) Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. New England Journal of Medicine 321: 357-362. Birkeland SA & Kristofferson K (1979) Pre-eclampsia--a state of mother-fetus imbalance. Lancet ii: 720--723. Branch DW & Scott JR (1990) Clinical implications of antiphospholipid antibodies: the Utah experience. In Harris EN (ed.) Phospholipid-Binding Antibodies (in press). Boca Raton, FA: CRC Press. Branch DW, Scott JR, Kochenour NK et al (1985) Obstetric complications associated with the lupus anticoagulant. New England Journal of Medicine 313: 1322-1326. Branch DW, Dudley D J, Mitchell MD et al (1990) IgG fractions from patients with antiphospholipid antibodies cause fetal death in Balb/c mice: a model for autoimmune fetal loss. American Journal of Obstetrics and Gynecology 163: 210-216. Buyon JP et al (1986) Serum complement values (C3 and C4) to differentiate between systemic lupus activity and pre-eclampsia. American Journal of Medicine 81: 194--200. Cariou R, Tobelem B, Soria C et al (1986) Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. New England Journal of Medicine 314: 1193-1194. Carreras LO, Vermylen J, Spitz B e t al (1981) 'Lupus' anticoagulant and inhibition of prostacyclin formation in patients with repeated abortion, intrauterine growth retardation and intrauterine death. British Journal of Obstetrics and Gynaecology 88: 890-894. Carreras LO, Perez GN, Vega HR et al (1988) Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet ii: 393-394. Cecere FA & Persellin RH (1981) The interaction of pregnancy and the rheumatic diseases. Clinics in Rheumatic Diseases 7: 747-768. Cowchock S, Dehoratius RD, Wapner RJ & Jackson LG (1984) Subclinical autoimmune disease and unexplained abortion'~ American Journal of Obstetrics and Gynecology 150: 367-371. Derkson RHWM, Brunise HW, Christiaens CrCML et al (1988) A controlled clinical trial on the efficacy of medicamentous treatment of pregnant patients with antiphospholipid antibodies--a preliminary report. Clinical and Experimental Rheumatology 6: 202. Druzin ML, Lockshin MD, Edersheim TG et al (1987) Second-trimester fetal monitoring and preterm delivery in pregnancies with systemic lupus erythematosus and/or circulating anticoagulant. American Journal of Obstetrics and Gynecology 157: 1503-1510. Dudley D J, Mitchell MD & Branch DW (1990) Pathophysiology of antiphospholipid antibodies: absence of prostaglandin-mediated effects on cultured endothelium. American Journal of Obstetrics and Gynecology 162: 953-959. Englert HJ, Derue GM, Loizou S et al (1988) Pregnancy and lupus: prognostic indicators and response to treatment. Quarterly Journal of Medicine 66: 125-136. Estes D & Larson D (1965) Systemic lupus erythematosus and pregnancy. Clinics in Obstetrics and Gynecology 8: 307-321. Fainstat T (1954) Cortisone-induced congenital cleft palate in rabbits. Endocrinology 55: 502. Fancourt R, Campbell S, Harvey D et al (1976) Follow-up studies of small-for-dates babies. British Medical Journal 1: 1435-1437.
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Feeney JG, Tovey LAC & Scott JS (1977) Influence of previous blood transfusion on the incidence of pre-eclampsia. Lancet i: 874-875. Gardlund B (1984) The lupus inhibitor in thromboembolic disease and intrauterine death in the absence of systemic lupus. Acta Medicina Scandinavia 215: 293-298. Hahn L, Norberg A, 8tigendal Let al (1988) The antiphospholipid antibody syndrome and pregnancy outcome--Swedish experiences. Clinical and Experimental Rheumatology 6: 204. Harger JH, Rabin BS & Marchese SG (1989) The prognostic value of antinuclear antibodies in women with recurrent pregnancy losses: a prospective controlled study. Obstetrics and Gynecology 73: 41%424. Harris EN (1987) Syndrome of the black swan. British Journal of Rheumatology 26: 324-326. Harris EN, Asherson RA, Gharavi AE et al (1985a) Thromboeytopenia in SLE and related disorders: association with antieardiolipin antibodies. British Journal of Haematology 59: 227-230. Harris EN, Gharavi A E & Hughes GRV (1985b) Antiphospholipid antibodies. Clinics in Rheumatic Diseases 11: 591-609. Johnson JWC, Mitzner W, London WT, Palmer AE & Scott R (1979) Betamethasone and the rhesus fetus: multisystem effects. American Journal of Obstetrics and Gynecology 133: 67%684. Kitzmiller JL (1977) Immunologic approaches to the study of preeclampsia. Clinical Obstetrics and Gynaecology 20: 717-735. Klipple GL & Riordan KK (1989) Rare inflammatory and hereditary connective tissue diseases. Rheumatic Disease Clinics of North America 15: 383-398. Klonoff-Cohen HS, Savitz DA, Cefalo RC & McCann MF (1989) An epidemiologic study of contraception and preeclampsia. Journal of the American Medical Association 262: 31433147. Kochenour NK, Branch DW, Rote NS et al (1987) A new postpartum syndrome associated with antiphospholipid antibodies. Obstetrics and Gynecology 69: 460--468. Koskela P, Vaarala O, Makitalo R et al (1988) Significance of false positive syphilis reactions and anticardiolipin antibodies in a nationwide series of pregnant women. Journal of Rheumatology 15: 70-73. Levitz M, Jansen V & Dancis J (1978) The transfer and metabolism of corticosteroids in the perfused human placenta. American Journal of Obstetrics and Gynecology 132: 363. Lockshin MD (1989) Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis and Rheumatism 32: 665-670. Lockshin MD, Reinitz E, Druzin ML et al (1984) Lupus pregnancy. Case control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. American Journal of Medicine 77: 893-898. Lockshin MD, Druzin ML, Goei Set al (1985a) Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. New England Journal of Medicine 313: 152-156. Lockshin MD, Harpel PC, Druzin ML et al (1985b) Lupus pregnancy II. Unusual pattern of hypocomplementemia and thrombocytopenia in the pregnant patient. Arthritis and Rheumatism 28: 58-66. Lockshin MD, Qamar T & Druzin ML (1987) Hazards of lupus pregnancy. Journal of Rheumatology 14(supplement 13): 214-217. Lockshin MD, Druzin ML & Qamar T (1989) Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. American Journal of Obstetrics and Gynecology 160: 43%443. Lockwood CJ, Reece EZ, Romero R et al (1986) Antiphospholipid antibody and pregnancy wastage. Lancet ii: 742-743. Lubbe WF, Butler WS, Palmer SJ & Liggins GC (1983) Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet i: 1361-1363. McFarlane A & Scott JS (1976) Pre-eclampsia/eclampsia in twin pregnancies. Journal of Medical Genetics 13: 108-121. Mintz G & Rodriquez-Alvarez E (1989) Systemic lupus erythematosus. Rheumatic Disease Clinics of North America 15: 255-274. Mintz G, Niz J, Gutierrez G e t al (1986) Prospective study of pregnancy in systemic lupus erythematosus: results of a multidisciplinary approach. Journal of Rheumatology 13: 732-739.
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Moore MP, Carter NP & Redman CWG (1983) Lymphocyte subsets in normal and preeclamptic pregnancies. British Journal of Obstetrics and Gynaecology 90: 326-331. Mowbray JF, Liddell H, Underwood JL et al (1985) Controlled trial of treatment of recurrent spontaneous abortion by immunization with paternal cells. Lancet i: 941-943. Need JA (1975) Pre-eclampsia in pregnancies by different fathers: immunological studies. British Medical Journal 1: 548-549. Need JA, Bell B, Meffin E & Jones WR (1983) Pre-eclampsia in pregnancies from donor inseminations. Journal of Reproductive Immunology 5: 329-338. Parke AL, Maier D, Wilson D, Andreoli J & Ballow M (1989) Intravenous gamma globulin, antiphospholipid antibodies and pregnancy. Annals oflnternal Medicine 110: 495-496. Persellin RH (1977) The effect of pregnancy on rheumatoid arthritis. Bulletin of the Rheumatic Diseases 27: 922-927. Redrnan CWG, Sargent IL & Stirrat GM (1982) Maternal cell-mediated immunity in normal and preeclamptic pregnancy. Clinical and Experimental Immunology 50: 601-609. Roberts JM, Taylor RN, Musci TJ et al (1989) Preeclampsia: an endothelial cell disorder. American Journal of Obstetrics and Gynecology 161: 12013-1204. Rosove MH, Tabsh K, Wasserstrum N et al (1990) Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstetricsand Gynecology 75: 630-634. Schiff E, Peleg E, Goldenberg M et al (1989) The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. New England Journal of Medicine 321: 351-356. Scott JS, Maddison PJ, Taylor PV et al (1983) Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. New EnglandJournalofMedicine309: 209-212. Scott JR, Rote NS & Branch DW (1987) Immunologic aspects of recurrent abortion and fetal death. Obstetrics and Gynecology 70: 645-656. Scott JR, Branch DW, Kochenour NK et al (1988) Intravenous globulin treatment of pregnant patients with recurrent pregnancy loss due to antiphospholipid antibodies and Rh isoimmunization. American Journal of Obstetrics and Gynecology 159: 1055-1056. Scott JS (1958) Pregnancy toxemia associated with hydrops fetalis, hydatiform mole and hydramnios. Journal of Obstetrics and Gynaecology of the British Commonwealth 65: 689-700. Sibai BM, Mirro R, Chesney CM & Leffler C (1989) Low-dose aspirin in pregnancy. Obstetrics and Gynecology 74: 551-557. Spargo B, Lichtig C, Luger AM et al (1976) The renal lesion in pre-eclampsia. Perspectives in Nephrology and Hypertension 5: 129-137. Sridama V, Yang S, Moawad A & DeGroot LJ (1983) T-cell subsets in patients with preeclampsia. American Journal of Obstetrics and Gynecology 147: 566-569. Stubbs TM, Lazarchik J & Horger EO (1984) Plasma fibronectin levels in pre-eclampsia: a possible biochemical marker for vascular endothelial damage. American Journal of Obstetrics and Gynecology 150: 885--887. Thacker SB & Berkelman RL (1985) Assessing the diagnostic accuracy and efficacy of selected antepartum surveillance techniques. Obstetrical and Gynecological Survey 41: 121-141. Thornton JG, Foote GA, Page GE et al (1987) False positive results of tests for syphilis and outcome of pregnancy: a retrospective case-control study. British Medical Journal 295: 355-356. Trudinger BJ & Giles WB (1989) Clinical and pathologic correlations of umbilical and uterine artery waveforms. Clinical Obstetrics and Gynaecology 32: 669-678. Trudinger BJ, Stewart GJ, Cook CM, Connelly A & Exner T (1988) Monitoring lupus anticoagulant-positive pregnancies with umbilical artery flow velocity waveforms. Obstetrics and Gynecology 72: 215-218. Varner MW, Meehan RT, Syrop CH et al (1983) Pregnancy in patients with systemic lupus erythematosus. American Journal of Obstetrics and Gynecology 145" 1025-1040. Wallenburg HCS, Makovitz JW, Dekker GA et al (1986) Low-dose aspirin prevents pregnancyinduced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet i: 1-3. Westwood M, Kramer MS, Munz D et al (1983) Growth and development of full-term nonasphyxiated small-for-gestational-age newborns: follow-up through adolescence. Pediatrics 71: 376-382. Zurier R (1989) Pregnancy in patients with rheumatic diseases. Rheumatic Disease Clinics of North America 15: 2.
