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Prenatal Cardiology
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Review paper

Management in maternal autoantibody-mediated clinical foetal myocardial disease

Julia Murlewska
,
Krzysztof Preis
,
Maciej Słodki
,
Iwona Strzelecka
,
Elżbieta Smolewska
,
Maria Respondek-Liberska

Prenat Cardio 2019
Online publish date: 2019/12/19
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Introduction

Connective tissue disease (CTD) is associated with a strong female predisposition and is often presented before or during reproductive years. Specialised issues in pregnancy management should be delivered in this patient group, which includes rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis (SSc), primary Sjogren’s syndrome (PSS), and inflammatory myositis (Table 1). In women with CTD early assessment of risk of pregnancy complications is very important. Detailed counselling concerning risk factors of poor pregnancy outcome, including consideration of relative contraindications to pregnancy (proper contraception) and appropriate planning for pregnancy, is required [1–10].
The best time for pregnancy initiation is during an inactive or stable phase of the disease. For decades, women with SLE were advised against pregnancy. High rates of poor outcome and risk for disease flare and lack of evidence for safe treatment proposals were established in pregnancy with lupus. Indeed, women with SLE/APS, RA, SSc have especially high rates of pregnancy complications, including: hypertensive disorders, including preeclampsia, intrauterine growth restriction (IUGR), foetal distress, foetal demise, placental insufficiency, caesarean deliveries, prematurity, premature rapture of membranes, and hospital admissions [2–10].
Pregnancy resulting in neonatal lupus syndrome (NL) with foetal cardiac manifestations, which represents passively acquired transplacental transfer of maternal anti-Ro/SSA (52 or 60 kD) or La/SSB (48 kD) antibodies (Table 2), may be the earliest signs of the disease in asymptomatic women [11–17]. Congenital heart block (CHB) is the most serious form of NL, affecting 2% of newborns of anti-Ro/La-positive women with CTD. The risk of CHB is increased when associated with maternal hypothyroidism or vitamin D deficiency and is 10-fold higher in women who have had a previously MAb-affected child [18–21]. Cardiac NL could also be demonstrated as more diffuse myocardial disease manifested as endocardial fibroelastosis (EFE), papillary muscle fibrosis, valvular disease calcifications of the atrial septum, mononuclear pancarditis, and cardiomyopathy (CM) with or without CHB [22, 23].
In case of foetal CHB it is worth remembering that, although very rare, causes other than maternal CTD may lead to CHB, which may require pacemaker implantation for the newborn baby. Left isomerism coexists more often with CHB. Logistic regression analysis confirmed that CHB associated with congenital heart defect (CHD) was the only one independent predictor of foetal death (p < 0.001) [24–31].

Management in asymptomatic women with autoimmune connective tissue diseases in pregnancies with foetal cardiac involvement

Any foetal heart rate abnormality, particularly bradycardia, should pay special attention and determine an urgent referral to a tertiary foetal cardiology centre. The detection of an early conduction defect such as prolonged PR interval should be importantly considered [32].
Indicated foetal echocardiography should be applied not only in foetal dysrhythmia, but also if there is suspected any foetal myocardial disease. Foetal cardiac abnormalities that may suggest maternal CTD are presented in Table 3.
Foetal CHB may be the first presentation of asymptomatic seropositive CTD in up to 50% of women [32]. Lopes et al. reported that late seroconversion of anti-Ro/La antibodies (MAb) is also possible in neonatal CHB. At the time of diagnosis of foetal CHB pregnant women were seronegative, but anti-Ro/anti-La antibodies were detected later, from one to eight years after the delivery in some cases [31].
In the involvement of positive maternal anti-Ro/SSA or anti--La/SSB antibodies titres should be checked every four weeks, and foetal echo is indicated weekly from 16 weeks of gestation upwards [33]. The obstetric management should be guided by the degree of cardiac failure noted on the echocardiography. An in utero environment with low-resistance circulatory pathways is preferred, as long as possible, to afford minimal work to maintain cardiac output and for the maturation of the lungs and other organs [34]. Laboratory tests for Rubella virus, Parvovirus, Coxackie virus, and Adenovirus, Cytomegalovirus should be implicated in foetal myocarditis [35].
In the recent analyses, registries, and national reviews 94.4% of CHBs were detected prenatally, there were no cases found before 18 weeks of gestation, and 90% were diagnosed before 30 weeks, with a median detection of 23 weeks [36].
Guidelines for the obstetric and rheumatologic management of the foetus identified with CHB have not been established; conversely, they are rather experimental [34, 36]. Therefore, our group decided to present our recommendations based on the current knowledge (Figure 1 and Table 4); however, it appears unlikely that appropriate treatment protocols to prevent CHB will be developed until the complicated pathophysiology of CHB is better understood and widely researched [20].
Hydroxychloroquine (HCQ) for CHB has been recommended by the European League Against Rheumatism EULAR during lupus pregnancies since 2007. HCQ has been shown to decrease the rate of neonatal cardiac involvement and reduce the risk of cardiac neonatal lupus in pregnant women who had foetal myocardial disease in a previous pregnancy [37–42] (Table 5).
There is only one registered non-randomised open-label study of hydroxychloroquine (Plaquenil) in the prevention of CHB, initiated in 2011 and still recruiting. Nineteen women meeting eligibility criteria: anti-Ro and/or anti-La Ab documented and with previous child with cardiac NL received 400 mg of Plaquenil per day, as soon as pregnancy was established. Mothers already on HCQ remained on 400 mg or were escalated to 400 mg if on 200 mg ≤10 weeks and might be followed with ≤ 20 mg of prednisone [43].
The study by Costedoat-Chalumeau et al. supported preliminary evidence for the safety of HCQ therapy during pregnancy. No visual, hearing, growth, or developmental abnormalities were reported in any of the children at the mean follow-up age of 26 months [44], although the potential effects of both retinal toxicity and ototoxicity have been reported in children [45–47].
From the evidence of foetal echocardiography, abnormalities such as : incomplete heart block, myocarditis, EFE, CM, decreased ventricular contractility, increased cardiac size, tricuspid regurgitation, pericardial effusion, ascites, or hydrops therapy with steroids (dexamethasone, betamethasone, prednisolone, pulse methyl prednisolone) should be proposed. Steroids cross the placenta, and might be generally recommended in the lowest effective doses for the shortest duration of time, usually for several weeks (Table 6). Fluorinated steroids were effective at reversing incomplete heart block, presumably due to ongoing inflammation, but third-degree block with fibrosis of the conduction system is potentially irreversible. The maternal side effects of steroids are not trivial and may include infection, osteoporosis/osteonecrosis, diabetes, and arterial hypertension. Foetal risks include intrauterine growth restriction, oligohydramnios and adrenal suppression [33, 43, 48–57] (Tables 6, 7).
Many studies do not support the effectiveness of monotherapy with steroids (≤ 20 mg per day) for foetuses with CHB. Intravenous immunoglobulin (IVIG) (400 mg/kg IVIG) and plasmapheresis ≤ 12 weeks of pregnancy through 24 weeks could be considered as candidate agents to reverse the progression of incomplete CHB/myocarditis/CM in addition to FS and decrease higher titres of maternal anti-SSA/Ro-SSB/La antibodies ≥ 50 U/ml correlated with the increased foetal risk (Table 8). The contraindications of the use of IVIG are: prior serious reaction to use of IVIG infusion, known IgA deficiency, and intolerance of volume load, e.g. congestive heart failure, nephrotic syndrome [58–66].
The attempt to increase the foetal heart rate to treat CHB has been approached, but such a therapy with sympathomimetics does not restore coordination of AV conduction on which the heart is dependent for adequate filling [62].
Low-dose aspirin is recommended, particularly in SLE pregnancy with nephritis, or positive antiphospholipid antibodies (aPL) to limit preeclampsia risk factors. In women with SLE-associated APS or primary APS, combination treatment with aspirin and heparin is also recommended, to decrease the risk of adverse pregnancy outcomes [67, 68].
Supplementation with vitamin D (< 4000 IU/day) and folic acid should be offered. Measuring blood vitamin D levels should be considered after pregnancy is confirmed. Influenza vaccination should be repeated every year to limit the risk of flares in the pregnancy, and secondary protection should be offered to infants during the first months of life. Annual ophthalmologic examinations should be performed to rule out HCQ retinopathy [69–71].
The final decisions about the time and the mode of delivery in pregnancies with MAb-mediated foetal myocardial diseases should be managed with strict cooperation between the obstetrician, rheumatologist, and foetal cardiologist, based on the obstetric circumstances, maternal state of the disease, and haemodynamic foetal sufficiency. Achieving a term delivery is the priority issue because the continued therapy, even in a foetus with CHB, cardiovascular score ≤ 7, and hydrops might ensure a better prognosis for the full-term newborn’s condition and for adequate pacemaker implantation. Anti-Ro/SSA or anti-La/SSB antibodies should be repeated after birth in the maternal serum and from the cord blood and in the newborn. Postnatal echocardiography and laboratory tests for Rubella virus, Parvovirus, Coxackie virus, Adenovirus, and Cytomegalovirus should be performed to exclude viral myocarditis, and targeted treatment must be coordinated [19, 30].

Conclusions

Foetal CHB may be the first presentation of asymptomatic CTD in up to 50% of women. All mothers of foetuses and infants with MAb-mediated myocardial disease should be echocardiographically screened. In the involvement of positive maternal anti-Ro/SSA or anti-La/SSB antibodies, foetal echo is indicated weekly from 16 weeks of gestation upwards. Polytherapy, rather than monotherapy with HCQ, steroids, IVIG, and plasmapheresis, to reverse the progression of the maternal autoantibody-mediated foetal cardiac disease, is recommended; however, appropriate treatment protocols cannot be developed because we are still waiting for the evidence-based results for their effectiveness. Similarly to the IVIG experience, HCQ data are inadequately small, and currently available evidence that these drugs reduce the risk of CHB appears insufficient. Our main goal, which is followed by contemporary progress in medicine and our knowledge is to prevent the occurrence of neonatal complete heart block and to diminish its consequences.

Conflict of interest

The authors declare no conflict of interest.

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Division of work:
Julia Murlewska (ORCID: 0000-0002-8266-4585): collection and/or assembly of data, data analysis and interpretation, writing the article
Krzysztof Preis (ORCID: 0000-0002-8097-3552): final approval
Maciej Słodki (ORCID: 0000-0002-0160-8013): critical revision, final approval
Iwona Strzelecka (ORCID: 0000-0003-3469-7064): critical revision, final approval
Elżbieta Smolewska (ORCID: 0000-0002-8421-0448): data analysis and interpretation, critical revision, final approval
Maria Respondek-Liberska (ORCID: 0000-0003-0238-2172): research concept and design, data analysis and interpretation, critical revision, final approval
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