Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism) 469 AFE. Although disputed on statistical grounds by Morgan [1] , this misconception persisted in some writings until recently. The historic anecdotal association between hypertonic uterine con- tractions and the onset of symptoms in AFE was further clarifi ed by the analysis of the National Registry [5] . These data demon- strated that the hypertonic contractions commonly seen in asso- ciation with AFE appear to be a result of the release of catecholamines into the circulation as part of the initial human hemodynamic response to any massive physiologic insult. Under these circumstances, norepinephrine, in particular, acts as a potent uterotonic agent [5,55] . Thus, while the association of hypertonic contractions and AFE appears to be valid, it is the physiologic response to AFE that causes the hypertonic uterine activity rather than the converse. Indeed, there is a complete ces- sation of uterine blood fl ow in the presence of even moderate uterine contractions; thus, a tetanic contraction is the least likely time during an entire labor process for any exchange between maternal and fetal compartments [56] . Oxytocin is not used with increased frequency in patients suffering AFE compared with the general population, nor does oxytocin - induced hyperstimulation commonly precede this condition [5] . Thus, several authorities, including the American College of Obstetricians and Gynecologists, have concluded that oxytocin use has no relationship to the occurrence of AFE [1,5,57] . A recent population - based cohort study of approximately 3 million deliveries in Canada reported a statistically signifi cant association of labor induction with AFE [58] , however the same investigators did not observe this associa- tion in another population - based cohort of approximately 3 million deliveries in the US [59] , casting doubt regarding any clinically signifi cant relationship between labor stimulation and AFE. The syndrome of AFE appears to be initiated after maternal intravascular exposure to various types of fetal tissue. Such expo- sure may occur during the course of normal labor and delivery; after potentially minor traumatic events, such as appropriate intrauterine pressure catheter placement; or during cesarean section. Because fetal - to - maternal tissue transfer is virtually uni- versal during the labor and delivery process, actions by healthcare providers, such as intrauterine manipulation or cesarean delivery, may affect the timing of the exposure. No evidence exists, however, to suggest that exposure itself can be avoided by altering clinical management. Simple exposure of the maternal circula- tory system to even small amounts of amniotic fl uid or other fetal tissue may, under the right circumstances, initiate the syndrome of AFE. This understanding explains the well - documented occur- rence of fatal AFE during fi rst - trimester pregnancy termination at a time when neither the volume of fl uid nor positive intrauter- ine pressure could be contributing factors [11] . Whereas much has been written about the importance to the fetus of an immu- nologic barrier between the mother and the antigenically differ- ent products of conception, little attention has been paid to the potential importance of this barrier to maternal well - being. The observations of the National Registry as well as cumulative data for the past several decades suggest that breaches of this barrier identical; fever is unique to septic shock, and cutaneous manifes- tations are more common in anaphylaxis. Nevertheless, the marked similarities of these conditions suggest similar patho- physiologic mechanisms. Detailed discussions of the pathophysiologic features of septic shock and anaphylactic shock are presented elsewhere in this text. Both of these conditions involve the entrance of a foreign sub- stance (bacterial endotoxin or specifi c antigens) into the circula- tion, which then results in the release of various primary and secondary endogenous mediators (Figure 35.3 ). Similar patho- physiology has also been proposed in non - pregnant patients with pulmonary fat embolism. It is the release of these mediators that results in the principal physiologic derangements characterizing these syndromes. These abnormalities include profound myocar- dial depression and decreased cardiac output, described in both animals and humans; pulmonary hypertension, demonstrated in lower primate models of anaphylaxis; and disseminated intervas- cular coagulation, described in both human anaphylactic reac- tions and septic shock [44 – 53] . Further, the temporal sequence of hemodynamic decompensation and recovery seen in experi- mental AFE is virtually identical to that described in canine ana- phylaxis [49] . An anaphylactoid response is also well described in humans and involves the non - immunologic release of similar mediators [44] . It is also intriguing that, on admission to hospital, 41% of patients in the AFE registry gave a history of either drug allergy or atopy [5] . The ability of arachidonic acid metabolites to cause the same physiologic and hemodynamic changes observed in human AFE has been noted [54] . Further, in the rabbit model of AFE, pre- treatment with an inhibitor of leukotriene synthesis has been shown to prevent death [28] . These experimental observations further support the clinical conclusions of the National AFE Registry analysis that this condition involves the anaphylactoid release of endogenous mediators, including arachidonic acid metabolites, which result in the devastating pathophysiologic sequence seen in clinical AFE [5] . Earlier anecdotal reports suggested a possible relationship between hypertonic uterine contractions or oxytocin use and Figure 35.3 Proposed pathophysiologic relation between AFE, septic shock, and anaphylactic shock. Each syndrome also may have specifi c direct physiologic effects. (Reproduced by permission from Clark SL, Hankins GVD, Dudley DA et al. Amniotic fl uid embolism: analysis of the national registry. Am J Obstet Gynecol 1995; 172: 1158 – 1169.) Chapter 35 470 opment of a consumptive coagulopathy, which may lead to exsanguination, even if attempts to restore hemodynamic and respiratory function are successful. It must be emphasized, however, that in any individual patient any of the three principal phases (hypoxia, hypotension, or coagulopathy) may either dom- inate or be entirely absent [5,38,61] . Clinical variations in this syndrome may be related to variations in either the nature of the antigenic exposure or maternal response. The differential diag- nosis is summarized in Table 35.3 . Maternal outcome is dismal in patients with AFE syndrome. In documented “ classic ” cases, the overall maternal mortality rate appears to be 60 – 80% [5,32] . Only 15% of patients survive neu- rologically intact. In a number of cases, following successful hemodynamic resuscitation and reversal of disseminated intra- vascular coagulation, life - support systems were withdrawn because of brain death resulting from the initial profound hypoxia. In patients progressing to cardiac arrest, only 8% survive neurologically intact [5] . In the National Registry database, no form of therapy appeared to be consistently associated with improved outcome. A large series of patients in whom the diag- nosis of AFE was obtained from the discharge summary reported a 26% mortality rate. Notably, however, many patients in this series lacked one or more potentially lethal clinical manifestation of the disease classically considered mandatory for diagnosis, thus casting the diagnosis into doubt. However, if one assumes that the discharge diagnosis of these patients was accurate, these data suggest improved outcome for those women with milder forms of the disease [61] . Samuelsson and colleagues [62] , using the Swedish Cause of Death Register, found that the case fatality rate for AFE was high and remained unaltered (42 – 48%) during the decades spanning the 1970s through 1990s. Reported maternal mortality rates are summarized in Table 35.4 . Neonatal outcome is similarly poor. If the event occurs prior to delivery, the neonatal survival rate is approximately 80%; only half of these fetuses survive neurologically intact [5] . Fetuses sur- viving to delivery generally demonstrate profound respiratory acidemia. Although at the present time no form of therapy appears to be associated with improved maternal outcome, there is a clear relationship between neonatal outcome and event - to - delivery interval in those women suffering cardiac may, under certain circumstances and in susceptible maternal – fetal pairs, be of immense signifi cance to the mother as well [5] . Previous experimental evidence in animals and humans unequivocally demonstrates that the intravenous administration of even large amounts of amniotic fl uid per se is innocuous [21,24,60] . Further, the clinical fi ndings described in the National Registry are not consistent with an embolic event as commonly understood (Table 35.2 ). Thus, the term “ amniotic fl uid embo- lism ” itself appears to be a misnomer. In the National Registry analysis, the authors suggested that the term “ amniotic fl uid embolism ” be discarded and the syndrome of acute peripartum hypoxia, hemodynamic collapse, and coagulopathy should be designated in a more descriptive manner, as “ anaphylactoid syn- drome of pregnancy. ” Clinical p resentation Clinical signs and symptoms noted in patients with AFE are described in Table 35.2 . In a typical case, a patient in labor, having just undergone cesarean delivery or immediately following vaginal delivery or pregnancy termination, suffers the acute onset of profound hypoxia and hypotension followed by cardiopulmo- nary arrest. The initial episode often is complicated by the devel- Table 35.2 Signs and symptoms noted in patients with amniotic fl uid embolism. Sign or symptom No. of patients (%) Hypotension 43 (100) Fetal distress * 30 (100) Pulmonary edema or ARDS † 28 (93) Cardiopulmonary arrest 40 (87) Cyanosis 38 (83) Coagulopathy ‡ 38 (83) Dyspnea § 22 (49) Seizure 22 (48) Atony 11 (23) Bronchospasm ¶ 7 (15) Transient hypertension 5 (11) Cough 3 (7) Headache 3 (7) Chest pain 1 (2) * Includes all live fetuses in utero at time of event. † Eighteen patients did not survive long enough for these diagnoses to be confi rmed. ‡ Eight patients did not survive long enough for this diagnosis to be confi rmed. § One patient was intubated at the time of the event and could not be assessed. ¶ Diffi cult ventilation was noted during cardiac arrest in six patients, and wheezes were auscultated in one patient. Reproduced by permission from Clark SL, Hankins GVD, Dudley DA. Amniotic fl uid embolism: analysis of a national registry. Am J Obstet Gynecol 1995; 172: 1158 – 1169. Table 35.3 Differential diagnosis of amniotic fl uid embolism. Air embolus Anaphylaxis Anesthetic toxicity Myocardial infarction Peripartum cardiomyopathy Placental abruption Pulmonary aspiration Septic shock Transfusion reaction Venous thromboembolism Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism) 471 cance of histologic fi ndings in patients with pulmonary fat embolism [68] . Other putative markers for AFE, such as serum tryptase [69] , pulmonary mast cell antitryptase [70] , serum TKH - 2 antibody to fetal antigen sialyl Tn [71] , pulmonary TKH - 2 antibody to fetal antigen sialyl Tn [72] , serum complement [69] , and plasma zinc coproporphyrin I [73] , have been studied but as of yet provide no defi nitive means of diagnosing or excluding AFE. Treatment For the mother, the end - result of therapy remains disappointing, with a high mortality rate. In the National Registry, we noted no arrest (Table 35.5 ) [5] . Similar fi ndings were reported by Katz et al. [63] in patients suffering cardiac arrest in a number of differ- ent clinical situations. Diagnosis In the past, histologic confi rmation of the clinical syndrome of AFE was often sought by the detection of cellular debris of presumed fetal origin either in the distal port of a pulmonary artery catheter or at autopsy [32] . Several studies conducted during the past decade, however, suggest that such fi ndings are commonly encountered, even in normal pregnant women (Figure 35.4 ) [64 – 67] . In the analysis of the National AFE Registry, fetal elements were found in roughly 50% of cases in which pulmonary artery catheter aspirate was analyzed and in roughly 75% of patients who went to autopsy [5] . The frequency with which such fi ndings are encountered varies with the number of histologic sections obtained. In addition, multiple special stains often are required to document such debris [32] . Thus, the diagnosis of AFE remains a clinical one; histologic fi ndings are neither sensitive nor specifi c. It is interesting to note that similar conclusions have been drawn regarding the diagnostic signifi - Table 35.4 Summary of published amniotic fl uid embolism case series. Series Methodology Period AFE Incidence (1 per x births) Maternal Mortality Morgan 1979 [1] Literature review 1926 – 1979 8,000 – 80,000 233/272 (86%) Hogberg 1985 [4] Swedish Birth Registry 1951 – 1980 83,000 * 8/12 (66%) * * Burrows [90] Royal Women ’ s Hospital, Brisbane, Australia 1984 – 1993 6,579 2/9 (22%) Clark 1995 [5] U.S. Registry 1988 – 1994 N/A 28/46 (61%) Gilbert 1999 [61] California population database of 1,094,248 singleton births 1994 – 1995 20,646 14/53 (26%) Tuffnell 2005 [89] U.K. Registry 1997 – 2004 N/A 13/44 (30%) Kramer 2006 [58] Canadian population based cohort of 3,018,781 deliveries 1991 – 2002 16,667 24/180 (13%) Samuelsson 2007 [62] Swedish Cause of Death Register from 2,961,000 deliveries 1973 – 1999 51,947 25/57 (44%) Abenhaim 2008 [59] U.S. population based cohort study of 2,940,362 births 1998 – 2003 12,987 49/227 (22%) * Incidence of fatal cases * * years 1972 – 1980 Table 35.5 Cardiac arrest - to - delivery interval and neonatal outcome. Interval (min) Survival Intact survival < 5 3/3 2/3 (67%) 5 – 15 3/3 2/3 (67%) 16 – 25 2/5 2/5 (40%) 26 – 35 3/4 1/4 (25%) 36 – 54 0/1 0/1 (0%) Reproduced by permission from Clark SL, Hankins GVD, Dudley DA. Amniotic fl uid embolism: analysis of the national registry. Am J Obstet Gynecol 1995; 172: 1158 – 1169. Figure 35.4 Squamous cells recovered from the pulmonary arterial circulation of a pregnant patient with class IV rheumatic mitral stenosis (magnifi cation, × 1000). From Clark 1986 [66] . Chapter 35 472 to the mother and deliver the baby [5,63] . For the pregnant patient, the standard ABC of cardiopulmonary resuscitation should be modifi ed to include a fourth category, D: delivery. New modalities for the treatment of AFE, such as high - dose steroids [5] , extracorporeal membrane oxygenation with intra - aortic balloon counterpulsation [74] , continuous hemodiafi ltra- tion [75,76] , cardiopulmonary bypass [77,78] , recombinant factor VIIa [79,80] , and nitric oxide [81] have been reported in survivors but are thus far of limited cumulative experience or demonstrated benefi t. There are limited data on risk of recurrence in a subsequent pregnancy for women who experience AFE; fewer than a dozen cases are reported in the published literature [82 – 87] . At present, it appears that the risk of recurrence is low. Despite many advances in the understanding of this condition, AFE or anaphylactoid syndrome of pregnancy remains enigmatic and in most cases is associated with dismal maternal and fetal outcomes, regardless of the quality of care rendered. Thus, AFE remains unpredictable, unpreventable, and, for the most part, untreatable. Further insight into this rare, but lethal, disorder may be forthcoming from the UK Obstetric Surveillance System (UKOSS), a joint initiative of the Royal College of Obstetricians and Gynaecologists and the National Perinatal Epidemiology Unit, which goal is to describe the epidemiology of a variety of uncommon disorders of pregnancy [88] . References 1 Morgan M . Amniotic fl uid embolism . Anaesthesia 1979 ; 34 : 29 . 2 Kaunitz AM , Hughes JM , Grimes DA . Causes of maternal mortality in the United States . Obstet Gynecol 1985 ; 65 : 605 . 3 Grimes DA . The morbidity and mortality of pregnancy: still a risky business . Am J Obstet Gynecol 1994 ; 170 : 1489 . 4 Hogberg U , Joelsson I . Amniotic fl uid embolism in Sweden, 1951 – 1980 . Gynecol Obstet Invest 1985 ; 20 ( 3 ): 130 – 137 . 5 Clark SL , Hankins GDV , Dudley DA , et al. Amniotic fl uid embolism: analysis of a national registry . Am J Obstet Gynecol 1995 ; 172 : 1158 . 6 Meyer JR . Embolia pulmonar amniocaseosa . Bras/Med 1926 ; 2 : 301 – 303 . 7 Steiner PE , Luschbaugh CC . Maternal pulmonary embolism by amni- otic fl uid . JAMA 1941 ; 117 : 1245 . 8 Liban E , Raz S . A clinicopathologic study of fourteen cases of amni- otic fl uid embolism . Am J Clin Pathol 1969 ; 51 : 477 . 9 Thomson WB , Budd JW . Erroneous diagnosis of amniotic fl uid embolism . Am J Obstet Gynecol 1963 ; 91 : 606 . 10 Resnik R , Swartz WH , Plumer MH , Benirschke K , Stratthaus ME . Amniotic fl uid embolism with survival . Obstet Gynecol 1976 ; 47 : 295 – 298 . 11 Guidotti RJ , Grimes DA , Cates W . Fatal amniotic fl uid embolism during legally induced abortion in the United States, 1972 – 1978 . Am J Obstet Gynecol 1981 ; 141 : 257 . 12 Cromley MG , Taylor PJ , Cummings DC . Probable amniotic fl uid embolism after fi rst trimester pregnancy termination . J Reprod Med 1983 ; 28 : 209 . difference in survival among patients suffering initial cardiac arrest in small rural hospitals attended by family practitioners compared with those suffering identical clinical signs and symp- toms in tertiary - level centers attended by board - certifi ed anesthe- siologists, cardiologists, and maternal – fetal medicine specialists. Nevertheless, several generalizations can be drawn. 1 The initial treatment for AFE is supportive. Cardiopulmonary resuscitation is performed if the patient is suffering from a lethal dysrhythmia. Oxygen should be provided at high concentrations. 2 In the patient who survives the initial cardiopulmonary insult, it should be remembered that left ventricular failure is commonly seen. Thus, volume expansion to optimize ventricular preload is performed, and if the patient remains signifi cantly hypotensive, the addition of an inotropic agent such as dopamine seems most appropriate. In patients who remain unstable following the initial resuscitative efforts, pulmonary artery catheterization may be of benefi t to guide hemodynamic manipulation. 3 Although no evidence exists to document the benefi t of corti- costeroids in patients with AFE, the similarities between AFE and anaphylaxis proposed in the National Registry suggest that the administration of high doses of corticosteroids could be a con- sideration. In the absence of any data to suggest the benefi t of this, however, steroid treatment is not mandated by standard of care; in fact since the original suggestion of corticosteroid therapy by the authors of the National Registry report, we have reviewed several cases where death resulted despite early high - dose steroid treatment. 4 In antepartum cases of AFE, careful attention must be paid to the fetal condition. In a mother who is hemodynamically unstable but has not yet undergone cardiorespiratory arrest, maternal con- siderations must be weighed carefully against those of the fetus. The decision to subject such an unstable mother to a major abdominal operation (cesarean section) is a diffi cult one, and each case must be individualized. However, it is axiomatic in these situations that where a choice must be made, maternal well - being must take precedence over that of the fetus. 5 In mothers who have progressed to frank cardiac arrest, the situation is different. Under these circumstances, maternal sur- vival is extremely unlikely, regardless of the therapy rendered. In such women, it is highly unlikely that the imposition of cesarean section would signifi cantly alter the maternal outcome. Even properly performed cardiopulmonary resuscitation (diffi cult at best in a pregnant woman) provides only a maximum of 30% of normal cardiac output. 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Clin Chem 1992 ; 38 : 526 – 529 . 74 Hsieh YY , Chang CC , Li PC , Tsai HD , Tsai CH . Successful application of extracorporeal membrane oxygenation and intra - aortic balloon counterpulsation as lifesaving therapy for a patient with amniotic fl uid embolism . Am J Obstet Gynecol 2000 ; 183 : 496 – 497 . 75 Weksler N , Ovadia L , Stav A , Ribac L , Iuchtman M . Continuous arteriovenous hemofi ltration in the treatment of amniotic fl uid embolism . Int J Obstet Anesth 1994 ; 3 : 92 – 96 . 475 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 36 Systemic Lupus Erythematosus and Antiphospholipid Syndrome T. Flint Porter 1 & D. Ware Branch 2 1 Department of Obstetrics and Gynecology, University of Utah Health Science UT and Maternal - Fetal Medicine, Urban Central Region, Intermountain Healthcare, Salt Lake City, UT, USA 2 Department of Obstetrics and Gynecology, University of Utah Health Sciences Center and Women and Newborns Services, Intermountain Healthcare, Salt Lake City, UT, USA Introduction Systemic lupus erythematosus (SLE) is a chronic infl ammatory condition that affects virtually every organ system. With an increased prevalence among women of reproductive age, it is the autoimmune disease most commonly encountered during preg- nancy. The majority of women with stable, uncomplicated SLE tolerate pregnancy well with relatively few serious obstetric com- plications. However, women with poorly controlled disease and/ or serious SLE - related end - organ disease are at substantial risk for maternal morbidity and even mortality, as well as several adverse obstetric outcomes. Antiphospholipid syndrome (APS) is another autoimmune condition associated with several adverse pregnancy outcomes. Anticoagulation prophylaxis reduces the risk of thromboembolism and fetal death but the incidence of pre - eclampsia, uteroplacental insuffi ciency, and preterm birth remain high. Management of both SLE and APS during pregnancy requires vigilance for signs and symptoms of disease exacerbation, aggres- sive immunosuppressive treatment when needed, and careful assessment of fetal well - being. A multidisciplinary approach is essential and should include the rheumatologist, obstetrician, and if renal disease is present, the patient ’ s nephrologist. Systemic l upus e rythematosus in p regnancy Background The prevalence of SLE varies depending on the population under study but generally ranges between 5 and 125 per 100 000 and affects women 5 – 10 times more often than men [1,2] . The peak age of onset in young women occurs between their late teens and early 40s [3] . The prevalence among ethnic groups, such as those with African or Asian ancestry, is highest and the disease appears to be more severe when compared to white patients. Familial studies indicate that genetic susceptibility to lupus involves several complex gene polymorphisms. Russell and colleagues [4] reported a linkage between susceptibility to lupus in family members and disequilibrium in polymorphisms located on the long arm of chromosome 1, 1q23 – 24. Genes coding for C - reactive protein (CRP), actively involved in apoptosis, have been mapped to this area and CRP levels are commonly low in patients with lupus. Another familial study suggested that a single nucleotide polymorphism within the programmed cell death 1 gene ( PDCD1 ) is associated with the development of the disease in both European and Mexican populations [5] . SLE e xacerbation ( fl are) d uring p regnancy Based on published reports, fl are occurs in about 30 – 60% of pregnant patients with lupus. Renal disease and disease activity appear to increase the rate of fl are during pregnancy. There is a split of opinion about whether pregnancy itself predisposes to lupus fl are [2] . All studies are hampered by the fact that many of the most common signs and symptoms of lupus fl are also occur in normal pregnancy. Some studies show higher rates of fl are in pregnant women compared to non - pregnant controls, even when disease is inactive at the time of conception [6 – 11] . Others report no difference in rates of fl are in women with well - controlled disease, whether treated or untreated, and non - pregnant women. [12 – 18] . Importantly, in nearly all studies, fl ares during preg- nancy are reported to be mild to moderate in nature and easily treated with glucocorticoids. Women with pre - existing renal disease, even when inactive, are undoubtedly at greatest risk for SLE fl are during pregnancy [3,9] . Pregnancy may predispose to deterioration of renal function, especially for women with active lupus nephritis (LN) and/or renal insuffi ciency before conception [19 – 21] . Tandon and col- leagues [22] reported that LN patients with inactive renal disease showed changes in disease activity and deterioration in renal function during pregnancy that were similar to those in non - pregnant patients with active LN. Overall, about one - third of Chapter 36 476 [21] and in 40% with pre - existing proteinuria as defi ned by > 300 mg/24 h or a creatinine clearance < 100 mL/min [30] . Not surprisingly, the most important risk factor for pregnancy loss in women with SLE is coexisting APS. In one series of preg- nant women with SLE, the presence of antiphospholipid antibod- ies had a positive predictive value for pregnancy loss of 50% [40] . In another, positive predictive value increased to over 85% if women with SLE also had a fetal death in a prior pregnancy [32] . Neonatal l upus e rythematosus Neonatal lupus erythematosus (NLE) is a rare condition of the fetus and neonate, occurring in 1 of 20 000 of all live births and in fewer than 5% of all women with SLE [41] . Dermatological NLE is most common and is described as erythematous, scaling annular or elliptical plaques occurring on the face or scalp, analo- gous to the subacute cutaneous lesions in adults. Lesions appear in the fi rst weeks of life, probably induced by exposure of the skin to ultraviolet light, and may last for up to 6 months [42] . Hypopigmentation may persist for up to 2 years. A small percent- age of affected infants will go on to have other autoimmune diseases later in life [42] . Hematological NLE is rare and may be manifest as autoimmune hemolytic anemia, leukopenia, throm- bocytopenia and hepatosplenomegaly. Cardiac NLE lesions include congenital complete heart block (CCHB) and the less frequently reported endocardial fi broelas- tosis. Endomyocardial fi brosis caused by NLE leads to interrup- tion of the conduction system, especially in the area of the atrioventricular node. The diagnosis is typically made around 23 weeks of gestation [43] when a fi xed bradycardia, in the range of 60 – 80 beats/min, is detected during a routine prenatal visit. Fetal echocardiography reveals complete atrioventricular dissociation with a structurally normal heart. The prognosis varies but in the most severe cases, hydrops fetalis develops in utero . Because the endomyocardial damage is permanent, a pacemaker may be nec- essary for neonatal survival. In the largest series of 113 cases diagnosed before birth, 19% died, of which 73% died within 3 months of delivery [43] . In that same series, the 3 - year survival was 79%. Cutaneous manifestations of NLE have also been reported in infants with CCHB [42] . Not all women who give birth to babies with NLE have been previously diagnosed with an autoimmune disorder [42,44] . However, in one study, 7 of 13 previously asymptomatic mothers who delivered infants with dermatologic NLE were later diagnosed with one of several autoimmune disorders [42] . Surprisingly, asymptomatic women who deliver infants with CCHB are less likely to later develop an autoimmune disorder than those with dermatologic manifestations alone [44] . Fetal immunologic damage is probably caused by maternal autoantibodies that cross the placenta and bind to fetal tissue [45 – 49] . Anti - Ro/SSA antibodies are found in 75 – 95% mothers who deliver babies with NLE [43,45,50] . A smaller percentage have anti - La/SSB, and some have both [50] . Dermatological NLE has also been associated with anti - U1RNP without anti - Ro/SSA or anti - La/SSB [50,51] . Of mothers with SLE who are serologi- women with renal disease experience fl are during pregnancy, fewer than 25% have worsening renal function, and only 10% of have permanent deterioration. Renal deterioration appears to be less severe in women with inactive LN in the 6 months before conception [9,14,19,21,23,24] . Pulmonary hypertension arises in up to 14% of patients with lupus, and even mildly raised pulmonary artery pressures can be seen in 37% of patients [25] . Though fortunately rare during pregnancy, pulmonary hypertension confers an unacceptably high risk of maternal death and patients should be counseled accordingly. Obstetric c omplications in w omen with SLE Women with SLE are at risk for several obstetric complications, sometimes resulting in serious maternal and perinatal morbid- ity. Between 20 and 30% of women with SLE have pregnancies complicated by pre - eclampsia [10,21,26] . Uteroplacental insuf- fi ciency resulting in intrauterine growth restriction (IUGR) or small for gestational age neonates occurs in 12 – 40% of lupus pregnancies [6,9,12,26,27] . The risk of IUGR is highest for women with renal insuffi ciency and/or hypertension [28,29] . Preterm birth is also more common in pregnancies complicated by SLE [7 – 10,12,26] . Most of preterm deliveries in women with SLE probably occur iatrogenically because of disease exacerba- tion and/or obstetric complications, though a higher risk of preterm premature rupture of membranes has been reported. The likelihood of serious obstetric complications is highest for women with poorly controlled disease, renal disease and/or chronic hypertension, and APS [10,21,27,28,31,32] . Chronic steroid use may also contribute to higher rates of pre - eclampsia and IUGR. Pregnancy loss is thought to be more prevalent among women with SLE, with rates ranging from 10 to 50% [11,16,17,29,33] . First - trimester loss occurs in about 20% of lupus pregnancies, not markedly higher than the general population [34] . However, still- birth (after 20 weeks of gestation) rates are elevated in several studies [9,14,21,35,36] . In one series, 20% of losses occurred during the second or third trimester [35] . Disease activity increases the likelihood of pregnancy loss [9,14] with one study reporting live births in 64% of women with active disease within 6 months of conception, compared to 88% in women with qui- escent disease [21] . In the Hopkins Lupus Pregnancy Cohort, increased lupus activity did not increase the risk for miscarriage, but the stillbirth rate was threefold higher [36] . The timing of lupus activity affects the pregnancy loss rate, with activity early in pregnancy being the most dangerous. Proteinuria, thrombo- cytopenia, and hypertension in the fi rst trimester are each inde- pendent risk factors for pregnancy loss. Women with these risk factors have a 30 – 40% chance of suffering a pregnancy loss [37] . Accordingly, pregnancy loss is more likely if SLE is diagnosed during the index pregnancy [38,39] . Renal insuffi ciency is also important; one group reported fetal loss in 50% of pregnancies complicated by moderate to severe renal insuffi ciency as defi ned by serum creatinine > 1.5 mg/dL Systemic Lupus Erythematosus and Antiphospholipid Syndrome 477 cally positive for anti - Ro/SSA antibodies, 15% will have infants affected with dermatological SLE; the proportion who deliver infants with CCHB is much smaller. However, once a woman with SLE and anti - Ro/SSA antibodies delivers one infant with CCHB, her risk for recurrence is at least two - to threefold higher than other women with anti - SSA/Ro - SSB/La antibodies who have never had an affected child [45] . There is no known in utero therapy that completely reverses fetal CCHB secondary to SLE. However, there is some evidence that treatment with glucocorticoids, plasmapheresis, intravenous immune globulin or some combination thereof, may slow the progression of prenatally diagnosed CCHB or at least prevent recurrence in a future pregnancy [52] . In utero treatment with dexamethasone was felt to slow disease progression in one case report of hydrops secondary to CCHB [53] . In one retrospective study, maternally administered dexamethasone appeared to prevent progression from second - degree block to third - degree block [54] . In a large series of 87 pregnancies at risk for NLE, mothers who received corticosteroids before 16 weeks of gesta- tion were less likely to deliver infants with CCHB compared to mothers who received no therapy [55] . However, there was no benefi t to treatment when CCHB was diagnosed in utero . In utero treatment with digoxin is not benefi cial for prenatally diagnosed CCHB [56] . Diagnosis of SLE and d etection of SLE e xacerbation ( fl are) Thorough and frequent clinical assessment remains essential for the timely and accurate detection of SLE fl are [2] . In pregnancy, detection is more diffi cult because many of the typical signs and symptoms associated with fl are are considered normal (Table 36.1 ). The SLE disease activity index (SLEDAI) has been modifi ed Table 36.1 Common symptoms in pregnancy that may mimic lupus fl are. Constitutional • Debilitating fatigue; may worsen throughout pregnancy Skin • Palmar erythema • Facial blush due to increased estrogen levels. Face • Melasma; photosensitive rash over cheeks and forehead Hair • Increased hair thickness and growth • Hair loss postpartum Pulmonary • Increased respiratory rate secondary to increased progesterone levels. • Dyspnea Musculoskeletal • Back pain ᭺ Relaxin loosens sacroiliac joint and pubis ᭺ Gravid uterus increases lumbar lordosis • Joint effusions Central Nervous System • Headache, normal in pregnancy as well as in preeclampsia Table 36.2 Preeclampsia versus Lupus Flare. Preeclampsia SLE Flare Risk Fac tors • 1 st Pregnancy Yes No • History of preeclampsia Yes No • Multiple gestation Yes No • Lupus nephritis Yes Yes • Gestational age After 20 weeks ’ Anytime Laboratory Findings • Urine sediment Negative Positive • Coombs Negative Sometimes positive • Complement (C3 & C4) Normal Usually low • Anti - DS DNA antibodies Negative Usually positive • Serum uric acid Elevated Normal Physical Findings • Rash Absent Sometimes present • Alopecia Absent Sometimes present • Mouth ulcers Absent Sometimes present • Arthritis Absent Sometimes present • Serositis Absent Sometimes present for pregnancy with several caveats to rule out normal pregnancy complications and thereby more accurately identify true SLE activity [2,43] ). The most common presenting symptom in both fl are and new onset disease is extreme fatigue. Fever, weight loss, myalgia and arthralgia are also very common [57] . In pregnancy, skin rashes are more frequent than musculoskeletal manifesta- tions [8] . Patients with LN exhibit worsening proteinuria along with pyuria, hematuria and urinary casts. Not surprisingly, SLE fl are in pregnant women with LN is easily confused with the development of pre - eclampsia/eclampsia syndromes (Table 36.2 ). Serological evaluation of SLE disease activity may be benefi cial in confi rming fl are in confusing cases. However, no study has found serial laboratory testing superior to thorough clinical assessment and if fl are is suspected, treatment should not be reserved only for women with positive serologic evaluation. Even so, the most specifi c serologic sign of SLE fl are is an elevation in anti - double - stranded DNA (anti - ds DNA) which precedes lupus fl are in more than 80% of patients [58 – 60] . In pregnancy, ele- vated anti - ds DNA titers have also been shown to correlate with the need for preterm delivery [61] and in combination with aCL antibodies, with an increased risk of fetal loss. Serial evaluation of complement levels has been suggested as method of predicting SLE fl are during pregnancy. Devoe [62] reported that SLE fl are was signaled by a decline of C3 and C4 into the subnormal range and Buyon [63] reported that the phys- iologic rise in C3 and C4 levels normally seen during pregnancy did not occur in women with active disease. The same group reported that activation of the alternative complement pathway Chapter 36 478 chronic glucocorticoid therapy are the same as in non - pregnant patients and include weight gain, striae, acne, hirsutism, immu- nosuppression, osteonecrosis and gastrointestinal ulceration. During pregnancy, chronic glucocorticoid therapy has also been associated with an increased risk of pre - eclampsia [35,73 – 75] , uteroplacental insuffi ciency [75] , and glucose intolerance [73,74] . Women chronically treated with glucocorticoids should be screened for gestational diabetes at 22 – 24, 28 – 30 and 32 – 34 weeks of gestation. Hydroxychloroquine Hydroxychloroquine (HCQ) has been proven to decrease the risk of SLE fl are, improve the prognosis of SLE nephritis, and prevent death [76 – 79] . It also has the lowest side - effect profi le of any medication available to treat SLE and is well tolerated by most patients. In the past, many patients and their physicians discon- tinued hydroxychloroquine in pregnancy because of concerns about teratogenicity including ototoxicity [80] and eye damage [81] . However, an accumulating body of evidence suggests that hydroxychloroquine can be used safely for the treatment of SLE during pregnancy [82 – 86] and is in fact superior to glucocorti- coids for women who require maintenance therapy during preg- nancy [87] . An expert panel of international physicians have recommended the continuation of HCQ during pregnancy [79] . Immunosuppressants Azathioprine (Imuran) is probably the safest immunosuppres- sant medication taken during pregnancy. The fetal liver does not have the enzyme required to metabolize azathioprine into its active form [79] . Series of pregnancies exposed to azathioprine for infl ammatory bowel disease or renal transplants show no signifi cant increase in fetal abnormalities among renal transplant patients. Nearly 40% of the offspring were small for gestational age. But this may also have been due to the underlying illness and/ or contemporaneous treatment with glucocorticoids [78,79] . Most authorities recommend continuation of azathioprine treat- ment during pregnancy [57] . Cyclophosphamide is reportedly teratogenic in both animal [88] and human studies [89,90] and should be avoided during the fi rst trimester. Thereafter, cyclo- phosphamide should be used only in unusual circumstances such as in women with severe, progressive proliferative glomerulone- phritis [1] . Methotrexate is well known to kill chorionic villi and cause fetal death and its use should be scrupulously avoided. NSAID p reparations The most common types of analgesics used in the treatment of SLE are non - steroidal anti - infl ammatory drugs (NSAIDs). Unfortunately, their use in pregnancy should be avoided after the fi rst trimester because they readily cross the placenta and block prostaglandin synthesis in a wide variety of fetal tissues. Though short - term tocolytic therapy with indomethacin appears to be safe [91,92] , chronic use has been associated with a number of untoward fetal effects and, when used after 32 weeks, may result in constriction or closure of the fetal ductus arteriosus [93] . accompanies fl are during pregnancy [63] and that a combination of low C3, C4, or CH50 levels accompanied by an elevation in complement split products is useful in detecting fl are during pregnancy [63] . The results of other studies of complement acti- vation in pregnant women with SLE have either been inconsistent or not predictive of SLE fl are [11,64,65] . Lockshin [66] reported normal concentrations of the Cls – C1 inhibitor complex in preg- nant patients with hypocomplementemia which suggests poor synthesis of complement components rather than excessive consumption. Laboratory confi rmation of SLE fl are is probably most helpful in women with active LN in whom proteinuria, hypertension and evidence of multiorgan dysfunction may easily be confused with pre - eclampsia. Both elevated anti - ds DNA titers and urinary sedi- ment with cellular casts and hematuria weigh in weigh in favor of active LN. An increase in proteinuria in women with pre - existing LN should not necessarily raise an alarm until it doubles [57] . Pre - eclampsia is more likely in women with decreased levels of antithrombin - III [67,68] . Complement concentrations are not helpful because activation may also occur in women with pre - eclampsia [69] . In the most severe and confusing cases, the diag- nosis can be confi rmed only with renal biopsy. However, in reality, concerns about maternal and fetal well - being often prompt delivery, rendering the distinction between the SLE fl are and pre - eclampsia clinically moot. Medications u sed for SLE d uring p regnancy Glucocorticoids The group of drugs most commonly given to pregnant women with SLE is the glucocorticoid preparations, both as maintenance therapy and in “ bursts ” to treat suspected SLE fl ares. The doses used in pregnancy are the same as those in non - pregnant patients. Pregnancy per se is not an indication to reduce the dose of glu- cocorticoids, though a carefully monitored reduction in dosage may be reasonable in appropriately selected women whose disease appears to be in remission. Some groups have recommended prophylactic glucocorticoid therapy during pregnancy [17,24,70] but no controlled studies have shown this practice to be prudent or necessary in women with inactive SLE. Moreover, good mater- nal and fetal outcomes are achieved without prophylactic treat- ment of women with stable disease [13] . In contrast, glucocorticoid treatment of women with active disease and/or elevated anti - ds DNA titers has been shown to result in fewer relapses and better pregnancy outcomes [14,58] . While glucocorticoids have a low potential for teratogenesis [71] , they are not without risk during pregnancy. Patients requir- ing chronic maintenance therapy are best treated with predniso- lone or methylprednisolone because of their conversion to relatively inactive forms by the abundance of 11 - ,B - ol dehydro- genase found in the human placenta. Glucocorticoids with fl uo- rine at the 9a position (dexamethasone, betamethasone) are considerably less well metabolized by the placenta and chronic use during pregnancy should be avoided. Both have been associ- ated with untoward fetal effects [72] . Maternal side effects of . Department of Obstetrics and Gynecology, University of Utah Health Science UT and Maternal - Fetal Medicine, Urban Central Region, Intermountain Healthcare, Salt Lake City, UT, USA 2 Department. the treatment of amniotic fl uid embolism . Int J Obstet Anesth 1994 ; 3 : 92 – 96 . 475 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy several cases where death resulted despite early high - dose steroid treatment. 4 In antepartum cases of AFE, careful attention must be paid to the fetal condition. In a mother who is hemodynamically