[PDF] Maternal Antiphospholipid Syndrome Presenting as Neonatal Lupus

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frequency of neonatalShigellainfectionis not well understood. The protectiveeffect of breast-feeding has been con-firmed in surveys of sporadic gastroen-teritis, in community epidemics, and inoutbreaks in newborn nurseries; howeverthis alone does not explain the resis-tance of infants to shigellosis since manyinfants are bottle-fed, as were ourpatients.Neonates with shigellosis can be a

source of infection to their surroundings.In the nursery the bacteria may spread toother infants as well as to hospital staff.Awareness of the infection, an aggressiveapproach to diagnosis, emphasis onhand-washing and the use of glovescontinue to be critical components of

infection control policy. Nonetheless, inat least one study it has been shown thatenteric isolation techniques failed tohalt the spread of shigellosis onceestablished [5]. Antimicrobial treatmentof all infected and uninfected patientswas required for control of the outbreak.The other simple measure to decrease

the risk of neonatal shigellosis spread is to support breast-feeding.Treatment of neonatal shigellosis consists of prompt supportive therapy such as hydration, correcting electrolyte imbalance, and good nutrition. It has been shown that proper antibiotic ther- apy shortens the duration of the disease and may halt the spread of the bacteria. More important is that such therapy maydecrease the rates of complications and mortality. The empiric choice of antibio- tics is dictated by susceptibility data on the strains circulating at the time patient

infection occurs. Currently in Israel, mostShigellastrains are resistant to ampicillinand trimethoprim-sulfamethoxazole andtherefore a third-generation cephalo-sporin should be administered in everyneonate suspected of suffering fromshigellosis.

References

1. Ferreccio C, Prado V, Ojeda A, Cayyazo M,Abrego P, Guers L, Levine MM. Epidemio-logical patterns of acute diarrhea andendemic

Shigellainfections in children in

a poor periurban setting in Santiago,Chile.Am J Epidemiol1991;134:614±27.2. Admoni O, Yagupsky P, Golan A, Kenes Y,Schifroni G, Horowitz I. Epidemiological,clinical and microbiological features ofshigellosis among hospitalized children innorthern Israel.

Scand J Infect Dis1995;27:139±44.3. Halatin RC. Neonatal shigellosis: Reportof 16 cases and review of the literature.

Am J Dis Child1967; 114:603±11.4. Bennish ML, Harris JR, Wojtyniak BJ,Struelens M. Death in shigellosis: inci-dence and risk factors in hospitalizedpatients.

J Infect Dis1990;161:500.5. Beers LM, Burke TL, Martin DB. Shigel-losis occurring in the newborn nurserystaff.

Infect Control Hosp Epidemiol1989;10:147±9.Correspondence:Dr A.S. Luder, Dept. ofPediatrics, Sieff Hospital, P.O. Box 1008,Safed, 13100, Israel.Phone: (972-4) 682-8712Fax: (972-4) 682-8647,email: luder@tx.technion.ac.il

Case Communications

Maternal Antiphospholipid Syndrome Presenting as NeonatalLupus with Congenital Complete Heart Block in the Fetus

Rasmi Abu-Ras MD

1 , Klari Felser MD2 and Menachem Rottem MD 3 1 Departments of Pediatrics A, HaEmek Medical Center, Afula, Israel 2 Department of Neonatology, HaEmek Medical Center, Afula, Israel 3 Division of Allergy and Clinical Immunology, HaEmek Medical Center, Afula, Israel

Key words:congenital heart block, antiphospholipid syndrome, antiphospholipid antibodies, pregnancycomplications, systemic lupus erythematosus, autoimmune disease

IMAJ 2001;3:966±968

Congenital heart block is a rare condi-tion that has been associated with thepresence of maternal antiphospholipidantibodies [1]. CHB occurs in 1:22 000 of

liveborn infants, and appears in 3.6% ofnewborns to mothers with known sys- temic lupus erythematosus. It is cur-rently considered an example of passively acquired autoimmunity, where-by maternal immune abnormalities lead to the production of autoantibodies crossing the placenta and presumably affecting an otherwise normally develop- ing fetus. In CHB, abnormal maternal immunization is thought to stimulateautoantibody production against SSA/Ro and SSB/La antigens. Antibodies to SSA/

Ro ribonucleoproteins in maternal sera

have been demonstrated almost univer- sally when CHB develops in an offspring[1]. The SSB/La antigen-antibody system is also strongly associated with the development of CHB [1]. These maternal antibodies are transferred via the pla- centa to the fetus and are believed to transmit irreversible immunological in- jury to the developing fetal heart tissue,thus causing third-degree atrioventricu- lar block. Although there is no unique antibody profile specific for CHB, women with a high or low risk of having a child with CHB can be identified. High levelsof anti-SSA/Ro and anti-SSB/La are associated with a significantly increased risk of having CHB. Female infantsCHB =congenital heart block

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appear to have an increased risk of CHB.The risk of having a subsequent childwith congenital heart block ranges be-tween 12 and 16% [2]. CHB is a seriouscondition with 60% of children requiringpacemakers, and 15±22% dying [1].Pregnancies at risk are difficult toidentify, since 66% of the mothers areasymptomatic at delivery.CHB and other neonatal abnormal-ities affecting the skin, liver, and bloodelements are grouped together underthe title "neonatal lupus syndromes."Neonatal lupus was so termed becausecutaneous lesions of the neonate re-sembled those seen in SLE. CHB isirreversible and is most commonly de-tected during the second trimester. Incontrast, the non-cardiac manifestationsof neonatal lupus are transient, resolvingduring the first 6 months of life, co-incident with the disappearance of ma-ternal autoantibodies from the maternalcirculation [1]. Owing to the presence ofantiphospholipid antibodies with recur-rent arterial and/or venous thrombosisand thrombocytopenia, it is referred toas antiphospholipid syndrome [3]. Ap-proximately 50% of these patients areconsidered to have primary APS and 50%secondary APS. Secondary APS seems tobe clinically indistinguishable from pri-mary APS except for an association withSLE. Recurrent fetal loss in non-SLEpatients represents the most frequentclinical presentation of primary APS inyoung women [3,4]. The frequency ofpregnancy loss in aPL-positive womenwithout a previous history of miscar-riage, thrombosis or thrombocytopeniais minimal. Most patients with incidentalaPL who are otherwise healthy haveuneventful pregnancies. Therefore, thepredictive aPL value for pregnancy com-plications in the general population isvery low. The presence of clinical man-ifestations of APS, and especially aprevious history of recurrent miscar-riages, make the finding of aPL verysignificant [3]. At the present time,however, the exact clinical criteria that

are sufficient to indicate screening or examination for aPL in preg- nant women are still unclear.

Conversely, it is not entirely clearhow CHB in the fetus in thepresence of aPL allows us tobetter diagnose the mother's con-dition.We report the case of a new-born who presented with a con-genital complete atrioventricularblock in the presence of aPL anddiscuss the above questions inthis context.

Patient Description

A healthy 32 year old, 30 week gravida

woman was sent to the emergency room by a community medical center nurse because of fetal bradycardia detected on

Doppler ultrasound. Her obstetric his-

tory was significant because of twoconsecutive spontaneous abortions inthe first trimester. The fetal bradycardiawas confirmed in the hospital and anemergency cesarean section was per-formed. A premature female baby wasborn weighing 1,200 g with an Apgarscore of 5/6 and severe bradycardia of 40beats/minute. Immediate resuscitationincluding repeated intratracheal adrena-lin and intravenous adrenalin was givenbut failed to raise the heart rate above60 beats/min, despite normal oxygensaturation. The infant was transferredto the neonatal intensive care unit andwas mechanically ventilated and treatedby intratracheal surfactant for respiratorydistress syndrome. Electrocardiographyshowed complete atrioventricular block[Figure A]. Another attempt to raise theheart rate with intravenous isoprel wasalso unsuccessful.Laboratory evaluation of the maternalserum showed the presence of lupusanticoagulant with prolonged activatedpartial thromboplastin time 40.7 sec(normal 25±37), PTT 40.2 sec (normal24±34), and PTT phospholipid serum41.7 sec (normal 27±35) in the presenceof anti-cardiolipin immunoglobulin M 15u/ml (normal 0±10) and absence of anti-

cardiolipin IgG. It revealed positive anti- nuclear antibodies of 0.656 (n = 0±

0.155), and autoantibodies to SSA/Ro,

borderline autoantibodies to SSB/La andabsence of autoantibodies to doublestranded-DNA, SM, RNP and SCL-70.Laboratory evaluation of the new-born's serum showed positive ANA of0.48 and SSA. There was absence of DSDNA, SSB, RNP, SCL-70 and anti-cardi-olipin IgG.At the age of 4 days she underwent apacemaker insertion and closure ofpulmonary ductus arteriosus. The heartrate was set to 120 beats/min [Figure B]and there were no postoperative com-plications. Following further treatmentfor her prematurity, the infant wasdischarged in stable condition weighing2,100 g at the age of 30 days.

Comment

Based on the last consensus classifica-

tion criteria for APS, the mother's con- dition in our case is compatible with

APS, although at the time of pregnancy

the criteria were not fully met. She hadhad two previous unexplained miscar-riages less than 10 weeks apart, and hadhigh titer of SSA/Ro. If the presentpregnancy had not been diagnosed andtreated, it could have ended in fetaldeath due to CHB.APS is related to all forms of fetalcomplications including intrauterinegrowth retardation and low birth weight[5]. The present case of a low birthweight female newborn with ANA and

Case Communications

SLE= systemic lupus erythematosusAPS = antiphospholipid syndromeaPL = antiphospholipid antibodies PTT = partial thromboplastin timeANA = anti-nuclear antibodies Electrocardiogram of newborn at birth[A]andafter pacemaker insertion[B].

967IMA

J .Vol 3.December 2001Neonatal Antiphospholipid Syndrome SSA/Ro antibodies is typical in itsclinical presentation

,with a more severeform of CHB that required a pacemakerinsertion.Recurrent pregnancy loss is one ofthe main features of APS [8], and the riskof a subsequent child with CHB is 18%[1]. While the predictive value of aPL forpregnancy complications is very low inthe general population [4], assay for SSA(anti-Ro) and SSB (anti-La) antibodiesshould be performed in the sera ofpregnant women with APS (as definedby the presence of aPL and the clinicalcriteria), or when CHB is detected in afetus of an asymptomatic pregnantwoman. The presence of clinical mani-festations of APS, and especially ahistory of recurrent miscarriages, makesthe finding of aPL very significant [3].Women with APS are at high risk forsubsequent pregnancy loss if untreated.Fetal loss, which is the most character-istic obstetric feature of APS and maylead to death in about 20% of cases, wasprevented in this case due to the earlydetection of fetal CHB. However, it isunclear precisely which clinical criteriaare sufficient to indicate screening orexamination for aPL in a pregnantwoman. It is recommended that allwomen with either SLE or APS be closelymonitored during pregnancy, as alsosuggested by others [4]. A completeautoantibody profile, including anti-DNA, anti-SSA/Ro, anti SSB/La, andaPL (anti-cardioplipin IgG and IgM andlupus anticoagulant) should be availablebefore or at least in early pregnancy [4].This, in turn, will lead to the appropriatemedical approach to both the fetus andthe mother and will prevent unnecessarycomplications that may culminate infetal death. It has, in fact, been sug-gested that all mothers with anti SSA/Roand/or SSB/La should have serial fetalechocardiography performed by an ex-perienced pediatric cardiologist andfocusing on gestational weeks 16±24 [1].This case indicates that asympto-matic SLE should always be suspectedin infants born with CHB. We proposebroadening the screening for early de-tection even when the mother does not

fulfill the full obstetric criteria for APS.

The obstetrician should be aware of APS

as a risk factor for two main reasons. The

first is to prevent premature birth of anuncompromised fetus by considering atrial treatment during pregnancy andavoiding unnecessary cesarean section.When persistent bradycardia is not asign of fetal distress, it can be the initialsign for a diagnosis of prenatal completeatrioventricular heart block. Echocardio-graphy, which is used to assess fetalhemodynamic status, may detect signsof fetal deterioration. Treatment strate-gies are debatable and may includeprophylactic therapy for high risk preg-nant women and a combination ofintrauterine plasmapheresis with plasmaexchange or with corticosteroids. Hy-drops fetalis and a further drop in theventricular heart rate warrant urgentcesarean section and pacemaker man-agement of the newborn. Second, iden-tification of autoimmune disease in thepregnant woman will lead to betterfollow-up and treatment of her owndisease. The management protocol mayinclude: planning of conception whendisease is inactive; frequent follow-upvisits by an internist-obstetrician team;use of sequential ultrasonographic, Dop-pler and fetal echocardiographic exam-inations; serial evaluations of maternalimmunological condition; and low doseaspirin beginning 1 month before at-tempting conception and throughoutpregnancy.The presence of ANA in the sera ofboth the mother and newborn is notentirely clear. Anti-nuclear antibodiesare not part of aPL [4], and theirpresence in sera is therefore not part ofAPS. While the criteria for SLE in themother were not present, it is possiblethat SLE may develop in the future. Theliterature support that some, but not all,mothers with CHB newborns may devel-op SLE [1]. Different series revealed that48±100% of asymptomatic mothers willdevelop rheumatic disease [1], althougha more recent study showed that only14% of asymptomatic mothers devel-oped rheumatic disease [1]. From thesestudies it can be concluded that asymp-

tomatic mothers do not invariably be- come ill, and that the specificity of anti-

SSA/Ro SSB/La antibodies is highly

stable for years, independent of thematernal clinical status. Since the new-born's condition is considered to beneonatal lupus syndrome, it can beargued that the presence of ANA sug-gests that the mother's condition ismore than APS. Neonatal lupus syn-drome is a passively acquired autoim-munity, where maternal autoantibodiescross the placenta and result in fetaltissuedamage[1].Thedisparityofdisease between mother and child,particularly in cardiac disease, under-scores the misleading nature of the term``neonatal lupus.''This case illustrates that neonatallupus syndrome presenting with CHB isa misnomer since it appears without anySLE in the mother. We propose ``neona-tal APS'' as a more suitable term.In conclusion, we suggest that CHBin the context of APS should be termedneonatal APS, and that screening preg-nant women should be broadened toinclude women who have aPL with someclinical characteristics of APS.

References

1. Tseng CE, Buyon JP. Neonatal lupussyndromes.

Rheum Dis Clinic North Am

1997;23:31±54.2. Meng C, Lockshin M. Pregnancy in lupus.

Curr Opin Rheumatol1999;11(51):348±51.3. Naguwa S, Robbins DL. Rheumatologicaldisorders. In: Delves PJ, Roitt IM, eds.Encyclopedia of Immunology. 2nd edn.London: Academic Press, 1998:2118±19.4. Ruiz-Irastorza G,. Khamashta MA, HughesGRV. Systemic lupus erythematosus andantiphospholipid syndrome duringpregnancy.

IMAJ2000;2:462±9.5. Granger KA, Fraquharson RG. Obstetricoutcome in antiphospholipid syndrome.

Lupus1997;6:509±13.Correspondence:Dr M. Rottem, Division ofAllergy and Clinical Immunology, HaEmekMedical Center, Afula 18101, Israel.Phone: (972-58) 617-823Fax: (972-4 659-3629email: rottem_me@clalit.org.il

Case Communications

968R. Abus-Ras et al.IMA

J .Vol 3.December 2001