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INTRODUCTION — Neonatal lupus (NL) is an autoimmune disease that is passively transferred from the mother to the fetus. The major manifestations are cardiac and cutaneous findings. The most serious complication of NL is complete heart block (approximately 20 percent have an associated cardiomyopathy at the initial diagnosis or develop it later [1,2]). In this topic review, the cardiac manifestations of NL are referred to as cardiac-NL and can include any degree of block (referred to as congenital heart block [CHB]) that may or may not be accompanied by extranodal disease such as valvular abnormalities, endocardial fibroelastosis, and/or dilated cardiomyopathy. Occasionally, those manifestations may occur in the absence of heart block.
This discussion emphasizes issues related to the treatment and potential prevention of NL. Testing for candidate antibodies is important prior to initiating therapy for a presumed case of cardiac-NL because there are cases of heart block not associated with anti-Ro/SSA (Sjögren syndrome type A antigen) or La/SSB (Sjögren syndrome type B antigen), and, thus, the management may be different. This testing is discussed separately. The specific indications for cardiac pacing in infants with congenital complete heart block are also discussed separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Screening and surveillance' and "Congenital third degree (complete) atrioventricular block".)
The epidemiology, pathogenesis, clinical manifestations, diagnosis, screening, and surveillance of NL are discussed in greater detail separately. Pregnancy in women with systemic lupus erythematosus (SLE) and diagnosis and management of fetal arrhythmias are also reviewed elsewhere. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Pregnancy in women with systemic lupus erythematosus" and "Overview of the general approach to diagnosis and treatment of fetal arrhythmias".)
IN UTERO MANAGEMENT — Complete heart block, once identified, is irreversible despite all therapies attempted to date, including glucocorticoids, apheresis, intravenous immune globulin (IVIG), and hydroxychloroquine [2-5]. Second-degree heart block may be reversible, but it also may progress to complete heart block despite therapy [4-7]. The clinical relevance of first-degree heart block is unclear since progression from first-degree block (defined as a PR interval longer than 150 msec) to more advanced heart block in untreated fetuses has not been well documented but can occur.
Efficacy and side effects of fluorinated glucocorticoids — Published data are limited and discordant regarding the efficacy of fluorinated glucocorticoids in reducing mortality in cardiac-NL. Dexamethasone and betamethasone, which are not inactivated by placental 11-beta dehydrogenase, may ameliorate pleuropericardial effusions or hydrops, and there are reports of improved outcomes [4,8-10]. However, there are risks of glucocorticoid therapy to both the mother (eg, infection, hypertension, avascular necrosis, insulin resistance, and gestational diabetes) and the infant (eg, oligohydramnios, growth restriction, and the still undetermined potential effect upon neurocognitive development) [11,12]. The use of fluorinated glucocorticoids for each degree of heart block is discussed in the sections below. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Glucocorticoids' and 'First-degree heart block' below and 'Second-degree heart block' below and 'Third-degree heart block' below.)
First-degree heart block — Treatment of isolated first-degree block (defined in some series as a PR interval >150 msec) with glucocorticoids in utero is controversial because of the risks of therapy, the evidence that first-degree block can revert to normal sinus rhythm (NSR) without therapy, and the inconsistent evidence that untreated first-degree block in the fetus can progress to more advanced block . The absence of substantial evidence is due in part to the fact that treatment is often provided to mothers with fetuses with first-degree block, and there is variability in both the technique of detection and cutoff values to define first-degree heart block among the different studies. In addition, if the block does revert to NSR with glucocorticoid treatment, it is unclear whether this supports continuing therapy for the remainder of the pregnancy.
Some centers prefer the watch-and-wait approach, while others treat all mothers whose fetuses have first-degree block [14-16]. The author's approach is to first confirm within 24 hours that the PR interval is indeed prolonged. If verified, the mother is started on oral fluorinated glucocorticoid (dexamethasone 4 mg per day or betamethasone 3 mg per day), and fetal monitoring by echocardiography is performed weekly. If there is progression to complete block and no evidence of extranodal disease, then dexamethasone is discontinued. If the block remains at first degree or reverts to NSR, then dexamethasone may be continued to 26 weeks gestation and then discontinued since vulnerability decreases after that time period and further inflammatory insult is less likely. However, other experts would not treat fetal first-degree block. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance for heart block'.)
Small, uncontrolled cases reports and series have shown that progression is rare, with the majority not progressing in the absence of treatment or resolving with treatment. In a Canadian study of 165 fetuses of 142 anti-Ro/La antibody-positive women referred for serial echocardiography, fetal atrioventricular (AV) prolongation or type 1 second-degree block (occurring in 15) were not treated, and none progressed . Other small studies and case reports showed normalization of AV conduction in one to two weeks in fetuses with first-degree heart block whose mothers were treated with dexamethasone [5,13,15,16]. Spontaneous resolution was seen in other case series [17,18]. Progression from first- to third-degree heart block was reported in only two cases [17,19].
Second-degree heart block — Most second-degree block detected in utero progresses to complete heart block [6,20,21]. In addition, it is hypothesized that incomplete block represents a reversible inflammatory state (more advanced than first-degree block and thus more clinically concerning) in which the AV node has not already been damaged and fibrosed. Thus, the goal of glucocorticoids in the case of second-degree block is twofold, decrease inflammation and prevent third-degree block, which is not reversible. However, second-degree block can revert to NSR without treatment, and not all cases respond to treatment. As such, prenatal treatment with fluorinated glucocorticoids (eg, oral dexamethasone 4 mg per day or betamethasone 3 mg per day) is suggested for mothers of fetuses with second-degree heart block, beginning as soon after detection as is feasible, as is monitoring with weekly echocardiography.
The challenge is the decision of when to stop such therapy. If the fetus improves, continuing therapy through the end of pregnancy is reasonable. However, discontinuation with vigilant observation (ie, weekly monitoring by echocardiography) is also an option since the vulnerability of the fetal heart decreases after 26 weeks gestation. If the fetus progresses to third-degree block or does not respond, discontinuation of therapy is reasonable if there is no other indication (eg, cardiomyopathy, myocarditis, hydrops) for treatment with glucocorticoids. However, this approach is not uniformly agreed upon, as many clinicians still worry about progression.
Small, uncontrolled case series document that both treated and untreated patients with second-degree block can progress, stabilize, or revert to NSR. In one report, four fetuses with second-degree heart block treated with dexamethasone or betamethasone reverted to first-degree block by birth . In contrast, two patients with second-degree heart block in utero who were not treated with fluorinated glucocorticoids progressed to complete heart block. Another study found that, of six fetuses with second-degree block treated with dexamethasone, three remained in second-degree block, two reverted to NSR, and one progressed to third-degree block . However, in a study from France, the use of glucocorticoids was not associated with regression of second-degree block in eight patients , and, in a Canadian study, 15 patients with type 1 second-degree block who were not treated did not progress .
Third-degree heart block — Complete heart block once documented does not revert and is associated with fetal demise in 5 to 20 percent [1,8,20,23]. Treatment of third-degree heart block with glucocorticoids in utero is somewhat controversial. It is generally not advised, unless there are other factors that indicate glucocorticoid treatment (eg, cardiomyopathy, endocardial fibroelastosis [EFE]), since reversal of third-degree block has not been documented  and most studies have not shown improved survival or prevention of the development of extranodal disease (eg, cardiomyopathy, EFE) [2,9,22]. Thus, management of the fetus with complete AV block is primarily expectant. Fetal echocardiography is usually performed weekly to look for extranodal disease. Postnatal management, including indications for pacemaker implantation, and mortality risk factors are discussed in detail separately. (See "Congenital third degree (complete) atrioventricular block", section on 'Post-natal treatment' and "Congenital third degree (complete) atrioventricular block", section on 'Prognosis' and 'Cardiomyopathy/endocardial fibroelastosis' below.)
Fluorinated glucocorticoids have not been shown to reverse third-degree block, as was demonstrated in a multicenter, open-label, nonrandomized study in which there was no reversal in 31 fetuses with third-degree heart block regardless of whether they were treated with glucocorticoids (n = 22) or not (n = 9) . In addition, most studies have not supported the use of fluorinated glucocorticoids to prevent disease progression or death. In a study of 202 cases of third-degree block reported from France, the use of fluorinated glucocorticoids was not associated with improved survival . In another retrospective study that included 71 fetuses with isolated advanced heart block in utero exposed to fluorinated glucocorticoids within one week of detection and 85 that were not treated, fluorinated glucocorticoids did not significantly prevent development of disease beyond the AV node, reduce mortality, or forestall/prevent pacemaker implantation .
Maternal beta-agonist therapy — Fetuses generally tolerate the arrhythmia well when ventricular rates are >55 beats per minute (bpm) in the absence of anomalies [24,25]. Administration of maternal beta-agonist therapy when the fetal heart rate is <50 to 55 bpm was shown to increase the heart rate and stroke volume in small case series [9,26]. Most centers use this approach routinely if the fetal heart rate is <50 bpm, although it has not been evaluated by comparative studies.
Indications for early delivery — Early delivery should be avoided unless there is evidence of poor overall health, intrauterine growth restriction, hydrops, or other indications since early delivery in the absence of these factors does not improve outcomes . At the time of labor, it is possible to monitor fetal wellbeing using the atrial rate as detected by Doppler devices normally used in fetal monitoring. A normal atrial rate with normal heart rate variability is reassuring. It is also possible to perform serial biophysical profile assessments or fetal pH measurements, if these resources are available. (See "Intrapartum fetal heart rate assessment" and "Management of intrapartum category I, II, and III fetal heart rate tracings" and "The fetal biophysical profile".)
Cardiomyopathy/endocardial fibroelastosis — Fluorinated glucocorticoids (eg, dexamethasone, betamethasone) and/or IVIG are often used if there is extranodal disease (eg, a more global cardiomyopathy). However, the effectiveness of these agents in the treatment of EFE is unclear . In an interinstitutional study from Toronto, a retrospective review of the use of glucocorticoids and IVIG, both in utero and after birth, suggested a potential survival benefit in cases with advanced heart block associated with cardiomyopathy/EFE (rate of demise at a median follow-up of three years was 20 percent compared with a rate of demise or need for cardiac transplant of 85 percent in historical controls) . A study from France reported five cases of anti-Ro-associated EFE without conduction abnormalities . Two mothers were treated with betamethasone, one chose to have a therapeutic abortion, and two chose no treatment. None of the electrocardiograms at birth (n = 4) showed heart block.
POSTNATAL MANAGEMENT — Post-natal management primarily depends upon what degree of heart block, if any, was noted in utero and what the findings are on initial neonatal electrocardiogram (ECG).
Infants and children at risk for complete heart block — An ECG should be performed on all neonates born to mothers with anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-La/SSB (Sjögren syndrome type B antigen) antibodies, even in the absence of any cardiac abnormalities detected with in utero monitoring. In addition, consultation with a pediatric cardiologist should be obtained if fetal monitoring has detected any degree of heart block in utero (including PR intervals >3 standard deviations [SD] or 150 msec, or second-degree block that reversed) and/or if the neonatal ECG is abnormal.
●First- or second-degree block identified after birth – Infants with first- or second-degree heart block identified after birth are at risk of postnatal progression to a higher-degree block, including complete heart block [6,20,21]. Thus, careful observation of these infants is necessary in the postnatal period under the oversight of a pediatric cardiologist.
●Transient in utero second-degree block – Infants with second-degree block in utero that reverted to normal sinus rhythm (NSR) and that have NSR at birth should be evaluated within the first three months of life by a pediatric cardiologist with performance of an ECG and echocardiogram as they are still at risk of developing third-degree heart block . The need for further monitoring can be assessed at that time.
●Transient first-degree block – Obtaining an echocardiogram and ECG at one year is a conservative approach for those with transient first-degree block, defined as PR prolongation >3 SD, in utero and a normal ECG at birth. In a study of 57 anti-Ro-exposed children, 6 (38 percent) of 16 with first-degree block in utero (using 2 SD, not 3 SD) who had NSR on birth ECG were found to again have first-degree block during preschool years . Conclusions based upon these data are limited in part by the less stringent cutoff of first-degree block to a 95 percent reference range.
●Noncardiac manifestations of NL after birth – Patients who are diagnosed with NL manifest as noncardiac involvement (rash or hematologic/liver abnormalities) after birth and have no evidence of heart block of any degree at birth (by exam and ECG) are unlikely to develop cardiac disease. For those who do, referral to cardiology is indicated.
The rash of NL generally does not cause scarring and disappears within six to eight months. Appearance of NL skin lesions postnatally is independent of breastfeeding [30,31]. Thus, breastfeeding is not contraindicated in mothers with anti-Ro/SSA and/or anti-La/SSB antibodies.
●No in utero or neonatal evidence of NL – Late de novo development of complete heart block is rare in children of women who test positive for Ro/SSA and La/SSB autoantibodies with no in utero conduction abnormalities and a normal ECG at birth. Thus, further cardiac surveillance is probably not justified in these children.
In a study of 57 anti-Ro-exposed children, none of the children with completely normal prenatal echocardiograms developed any conduction abnormality . However, several cases of postnatal de novo complete heart block were identified in a retrospective study , and rare cases of isolated cardiomyopathy (one fatal) have been reported in the Research Registry for Neonatal Lupus. Although a normal pre- and/or perinatal heart rhythm was confirmed in the patients in the retrospective series, the shortcoming of this observation is the absence of frequent serial in utero echocardiographic surveillance, which may have revealed a transient or incomplete block that went clinically undetected.
Complete heart block — Some infants with complete heart block require insertion of a cardiac pacemaker, especially if the heart rate at delivery is less than 55 beats per minute (bpm). Infants and young children with complete heart block who are asymptomatic usually end up requiring a pacemaker later in childhood, adolescence, or adulthood. However, exercise limitation and even death are possible in the absence of pacing. The prognosis following pacemaker implantation is excellent for most children, although development of heart failure may occur. The postnatal management and prognosis of complete heart block are discussed in greater detail separately. (See "Congenital third degree (complete) atrioventricular block", section on 'Post-natal treatment' and "Congenital third degree (complete) atrioventricular block", section on 'Prognosis'.)
NL rash — The rash associated with NL typically resolves by six to eight months of age without sequelae. Thus, treatment is not required. However, treatment with topic corticosteroids may hasten the resolution of lesions [33,34]. Sun protection is also advised, including avoidance of direct sunlight and fluorescent light. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection".)
Adrenal insufficiency — Prolonged in utero exposure to fluorinated glucocorticoids (eg, betamethasone or dexamethasone) can lead to adrenal hypoplasia and result in neonatal adrenal insufficiency . This is a rare complication that can be anticipated and for which neonates can be tested. Neonatal hypotension that potentially results from adrenal insufficiency should be treated empirically with hydrocortisone in addition to standard supportive care. The diagnosis and treatment of adrenal insufficiency are discussed in greater detail separately. (See "Diagnosis of adrenal insufficiency in children" and "Treatment of adrenal insufficiency in children".)
Autoimmune and/or rheumatic disease — Children who have had NL may be at increased risk of developing an autoimmune and/or rheumatic disease, albeit this is rare. In a cohort of 49 children followed to at least the age of eight years, six patients (12 percent) developed a well-defined systemic rheumatic and/or autoimmune disease . The disorders noted in these children included oligoarticular and polyarticular juvenile idiopathic arthritis, psoriasis, thyroid disease, iritis, type 1 diabetes mellitus, and nephrotic syndrome. None of the children with neonatal disease, nor any of their unaffected siblings, developed systemic lupus erythematosus (SLE) during at least eight years of follow-up.
PREVENTION OF NL IN SUBSEQUENT PREGNANCIES — Hydroxychloroquine is an antimalarial drug that inhibits ligation of endosomal Toll-like receptors (TLRs). It is one of the drugs used to treat systemic lupus erythematosus (SLE) and is often continued during pregnancy because it is associated with minimal risk to the fetus and mother. Data suggest it may also decrease the risk of the fetus developing cardiac-NL when there is a prior history of cardiac-NL in a sibling. The efficacy in the setting of prior cutaneous-NL is not known. Thus, we suggest pre-emptive treatment with hydroxychloroquine (400 mg orally once a day) in pregnant women with anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-La/SSB (Sjögren syndrome type B antigen) antibodies who have previously given birth to a child with cardiac-NL, regardless of maternal health status. Hydroxychloroquine is initiated between 6 and 10 weeks gestation in women who are not already on the medication to optimize effective exposure by 16 weeks of gestation. Pre-emptive treatment is not used if there is only a history of noncardiac-NL. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation" and "Pregnancy in women with systemic lupus erythematosus", section on 'Selective use allowed during pregnancy'.)
Several retrospective studies have suggested that hydroxychloroquine decreases the overall risk of cardiac-NL [37-39]. One retrospective study based upon data from NL registries in the United States, France, and the United Kingdom included pregnancies of women who had previously given birth to a child with cardiac-NL and had anti-Ro/SSA antibodies, regardless of maternal health status (ie, the mother could have been asymptomatic at the time of pregnancy or have had an associated autoimmune disease) . Two-hundred fifty-seven pregnancies (40 exposed and 217 unexposed to hydroxychloroquine) were identified. Cardiac-NL developed in 3 of 40 (7.5 percent) of exposed fetuses and 46 of 217 (21.2 percent) of unexposed fetuses, with 10 fatalities in the unexposed group. Another retrospective, single-center study examined 268 pregnancies, 73 of which had exposure to hydroxychloroquine throughout the pregnancy . Ninety-nine offspring developed cardiac NL, with a nonsignificant trend toward a protective effect of hydroxychloroquine on cardiac NL. A prospective, open-label study (not randomized because of the rarity of the disease) to confirm these observations is ongoing (clinicaltrials.gov).
Preventive treatment with glucocorticoids is not recommended, even in mothers with a previously affected fetus, because the risks of these medications in the majority of expectant mothers and their fetuses who would be unnecessarily exposed outweigh the uncertain potential benefits.
Intravenous immune globulin (IVIG) is also not recommended. In two multicenter, prospective, observational studies, IVIG at replacement doses (400 mg/kg) given every three weeks from weeks 12 to 24 was not effective in preventing congenital heart block (CHB) [40,41]. It is unknown whether higher anti-inflammatory (1 to 2 g/kg) doses would be efficacious.
SUMMARY AND RECOMMENDATIONS
●Neonatal lupus (NL) is a passively acquired autoimmune disease that occurs in offspring of mothers with anti-Ro/SSA (Sjögren syndrome type A antigen) and/or anti-La/SSB (Sjögren syndrome type B antigen) antibodies. The most serious complication of NL is complete heart block. (See 'Introduction' above.)
●Prenatal treatment of first-degree block is perhaps the most controversial because of the risks of therapy and absence of consistent evidence regarding benefit. We would first confirm within 24 hours that the PR interval is indeed prolonged (>150 msec). If verified, we suggest starting the mother on a fluorinated glucocorticoid (oral dexamethasone 4 mg per day or betamethasone 3 mg per day) (Grade 2C). The glucocorticoid is discontinued if there is progression to complete block and no evidence of extranodal disease. If the block remains at first degree or reverts to normal sinus rhythm (NSR), then the glucocorticoid is continued to 26 weeks gestation and then stopped since vulnerability decreases after that time period and further inflammatory insult is less likely. Observation rather than treatment is a reasonable alternative. (See 'First-degree heart block' above.)
●We suggest prenatal treatment with fluorinated glucocorticoids (oral dexamethasone 4 mg per day or betamethasone 3 mg per day) for mothers of fetuses with second-degree heart block, beginning as soon after detection as is feasible (Grade 2C). Therapy is usually continued through the end of pregnancy if the heart block reverts, although discontinuation after 26 weeks (less vulnerable period) is also reasonable. Glucocorticoids are typically discontinued if the fetus progresses to third-degree heart block or does not improve if there is no other indication for treatment with glucocorticoids (eg, cardiomyopathy, myocarditis), although continuing therapy through the end of pregnancy is also reasonable. (See 'Second-degree heart block' above.)
●Reversal of prenatal third-degree block with glucocorticoid therapy has not been documented, and most studies suggest treatment with glucocorticoids does not improve survival or prevent the development of extranodal disease. Thus, we suggest against treating in utero third-degree block without any signs of myocarditis or cardiomyopathy with glucocorticoids (Grade 2C). Most of these patients will require cardiac pacing after birth. (See 'Third-degree heart block' above and "Congenital third degree (complete) atrioventricular block".)
●An electrocardiogram (ECG) should be performed on all neonates born to mothers with anti-Ro/SSA and/or anti-La/SSB antibodies, even in the absence of any cardiac abnormalities detected with in utero monitoring. In addition, a pediatric cardiologist should be consulted for further evaluation including echocardiograms and additional ECGs if fetal monitoring has detected any degree of heart block in utero (including PR intervals >3 standard deviations [SD] or 150 msec, or second-degree block that reversed) and/or if the neonatal ECG is abnormal. (See 'Infants and children at risk for complete heart block' above.)
●There appears to be no risk of later cardiac involvement in patients who have no evidence of heart block of any degree in utero or at birth. Second-degree block detected in utero or at birth can progress to complete heart block. Infants and young children with complete heart block usually require a pacemaker at some point in life. The prognosis following pacemaker implantation is excellent for most children, although development of heart failure may occur despite the complete clearance of maternal autoantibodies from the child's circulation. The rash of NL generally does not cause scarring and disappears within six to eight months. (See 'Postnatal management' above and "Congenital third degree (complete) atrioventricular block", section on 'Prognosis'.)
●We suggest pre-emptive treatment with hydroxychloroquine (400 mg orally once a day) in pregnant women who have previously given birth to a child with cardiac manifestations of NL (cardiac-NL) and who have anti-Ro/SSA and/or anti-La/SSB antibodies, regardless of maternal health status (Grade 2B). Hydroxychloroquine should be initiated between 6 and 10 weeks gestation in women who are not already on the medication. (See 'Prevention of NL in subsequent pregnancies' above.)
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