Questions about dexamethasone use for the prevention of anti-SSA related congenital heart block

Abstract

Mothers with anti-SSA/Ro antibodies who have had a previous fetus with congenital heart block (CHB) have a risk of recurrence estimated to be up to 16%.
To improve the management of these "high risk patients" by determining (a) whether or not prophylactic treatment is efficient; (b) whether or not fluorinated steroids (betametasone and dexamethasone) that do cross the placenta in an active form are safe for the fetus; and (c) which prophylactic treatment should be used.
Retrospective study performed on seven mothers sent to a university hospital owing to a past history of one (six mothers) or two children (one mother) with CHB.
13 subsequent pregnancies occurred. No CHB was observed. All four pregnancies in women treated with 10 mg/day prednisone were uneventful. Three pregnancies in women receiving no steroids resulted in two early spontaneous abortions and one live birth. The six pregnancies in women treated with dexamethasone (4-5 mg/day) ended in one early and one late spontaneous abortion, two stillbirths, and two live births with intrauterine growth restriction and mild adrenal insufficiency. A histological study of one stillbirth disclosed intrauterine growth restriction and marked adrenal hypoplasia.
Adverse obstetric outcomes were often seen here and major concerns have been raised by paediatricians about the safety of fluorinated steroids, owing to the results of animals studies, retrospective data, and randomised trials. Because fluorinated steroids have not been shown to improve prophylactic treatment of CHB in pregnant women at high risk, their use is questionable.

Full text

CONCISE REPORT
Questions about dexamethasone use for the prevention
of anti-SSA related congenital heart block
N Costedoat-Chalumeau, Z Amoura, D Le Thi Hong, B Wechsler, D Vauthier,
P Ghillani, T Papo, O Fain, L Musset, J-C Piette
.............................................................................................................................
Ann Rheum Dis
2003;62:1010–1012
Background: Mothers with anti-SSA/Ro antibodies who
have had a previous fetus with congenital heart block
(CHB) have a risk of recurrence estimated to be up to 16%.
Objective: To improve the management of these “high risk
patients” by determining (
a
) whether or not prophylactic
treatment is efficient; (
b
) whether or not fluorinated steroids
(betametasone and dexamethasone) that do cross the pla-
centa in an active form are safe for the fetus; and (
c
) which
prophylactic treatment should be used.
Methods: Retrospective study performed on seven mothers
sent to a university hospital owing to a past history of one
(six mothers) or two children (one mother) with CHB.
Results: 13 subsequent pregnancies occurred. No CHB
was observed. All four pregnancies in women treated with
10 mg/day prednisone were uneventful. Three pregnan-
cies in women receiving no steroids resulted in two early
spontaneous abortions and one live birth. The six pregnan-
cies in women treated with dexamethasone (4–5 mg/day)
ended in one early and one late spontaneous abortion,
two stillbirths, and two live births with intrauterine growth
restriction and mild adrenal insufficiency. A histological
study of one stillbirth disclosed intrauterine growth restric-
tion and marked adrenal hypoplasia.
Conclusion: Adverse obstetric outcomes were often seen
here and major concerns have been raised by paediatri-
cians about the safety of fluorinated steroids, owing to the
results of animals studies, retrospective data, and
randomised trials. Because fluorinated steroids have not
been shown to improve prophylactic treatment of CHB in
pregnant women at high risk, their use is questionable.
P
regnant women with anti-SSA/Ro antibodies are at risk of
delivering an infant with neonatal lupus syndrome. Neo-
natal lupus syndrome is characterised by transient lupus
der matitis, hepatic and haematological abnormalities, or
isolated congenital heart block (CHB).
1
The heart block is per-
manent, often requires a pacemaker,
1
and may be complicated
by late onset cardiomyopathy. If anti-SSA/Ro antibodies are
present in the sera of pregnant women, the incidence of CHB
in live births has been reported to be 2% in a recent prospec-
tive study.
2
By contrast, the risk of recurrence of CHB in a sub-
sequent child is estimated to be up to 16%.
1
Attention has been focused on two different points: in utero
treatment of established CHB and prophylactic treatment of
mothers with anti-SSA/Ro antibodies to prevent the occur-
rence of CHB. Clearly, treatment is needed for the former
because of the substantial morbidity and mortality of CHB.
Increasing data indicate that treatment with fluorinated ster-
oids (dexamethasone or betamethasone) that do cross the
placenta in an active form is useful for fetuses with
incomplete block or hydropic changes.
3
It remains unclear
whether treatment started immediately upon detection of a
third-degree block is useful. Accordingly, Buyon et al have pro-
posed guidelines for in utero treatment of established CHB.
4
The problem of prophylactic treatment of CHB in pregnant
patients with anti-SSA/Ro antibodies is less clear owing to the
rarity of this complication. Shinohara et al have suggested that
prenatal maintenance treatment with prednisolone or beta-
methasone given to the mother with anti-SSA/Ro antibodies
and starting before 16 weeks’ gestation might reduce the risk
of developing CHB in the offspring.
5
However, the retrospec-
tive nature of the study and potential referral bias preclude
any firm conclusions. Additionally, the authors did not differ-
entiate between prednisolone and betamethasone and consid-
ered that both treatments were efficient to prevent CHB. If
equivalent to betamethasone, prednisone and prednisolone
should be preferred, as they do not cross the placenta, and
thus, would not affect the fetus. However, numerous case
reports or series have described the occurrence of CHB despite
prednisone or prednisolone treatment (unpublished data and
the following references).
367
Then, fluorinated steroids that
do cross the placenta in an active form may be theoretically
prefer red. During the “Fourth international workshop on
neonatal lupus syndromes and the Ro/SSA-La/SSB system”
8
a
protocol with randomisation of dexamethasone to anti-Ro
positive mothers who had had no previous fetuses with CHB
was proposed. This suggestion was controversial and stimu-
lated considerable comment and debate among the rheuma-
tologists attending the meeting. By contrast, dexamethasone
or betamethasone prophylactic treatment of mothers who had
had a previous fetus with CHB and were therefore at high risk
of recurrence was proposed.
8
However, little is known about
the safety and effectiveness of this intervention.
We report our experience in prophylactic treatment used for
pregnant women with anti-SSA/Ro antibodies who had had a
previous fetus with CHB and we discuss the adverse effects of
dexamethasone.
PATIENTS AND METHODS
Patients
This monocentric and retrospective study was performed in
Pitié-Salpêtrière University hospital in France. Seven mothers
were referred for a prior history of one (six mothers) or two
children (one mother) affected by CHB (table 1). In all cases,
CHB revealed the maternal anti-SSA/Ro antibodies status.
Subsequently, these mothers were regularly monitored in our
centre before becoming pregnant. During follow up, two
patients met the American College of Rheumatology criteria
for systemic lupus erythematosus (SLE), four met the
European criteria for primary Sjögren’s syndrome (SS), and
one remains symptom free. Between January 1993 and Janu-
ary 2002, 13 subsequent pregnancies occurred spontaneously
in these seven women. The mean age at pregnancy onset was
35 years (range 27–42). During pregnancy, patients were
closely monitored by both an inter nist and a high risk
pregnancy obstetric team, monthly until 32 weeks and then
1010
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every two weeks. Instrumental monitoring included repeated
fetal echocardiography and Doppler velocimetry (every two
weeks between 16 and 26 weeks’ gestation).
Autoantibody determination status
Serum samples were tested using INNO-LIAT ANA Update
(Innogenetics, provided by InGen, France), a semiquantitative
line immunoassay for detection of antibodies against Ro 52
kDa, Ro 60 kDa, and La. All patients were positive for
anti-SSA/Ro 52 kDa antibodies, six for anti-SSA/Ro 60 kDa
antibodies, and six for anti-SSB/La antibodies. Autoantibody
status did not change during follow up.
Treatments and follow up
Treatment was not standardised. Upon the diagnosis of preg-
nancy, patients received either 10 mg/day of prednisone
(number of pregnancies 4), dexamethasone with a daily dose
of 4 mg (n=3), 4.5 mg (n=2) or 5 mg (n=1), or no glucocor-
ticoids (n=3) (table 1). Associated treatments were 100
mg/day aspirin (n=9) and hydroxychloroquine (n=7).
RESULTS
The outcome of the 13 pregnancies included four spontaneous
abortions, two stillbirths, and seven live births (table 1).
Repeated fetal echocardiography and Doppler velocimetry
were performed in all cases and no CHB was seen. For the
stillbirths, fetal echocardiography results were available
within two weeks before birth and were normal. No other fea-
ture of neonatal lupus syndrome was noticed in the live births.
All four pregnancies in women treated with prednisone were
uneventful. The three pregnancies in women receiving no
steroids resulted in two early spontaneous abortions and one
live birth. The six pregnancies in women treated with dexam-
ethasone ended in two spontaneous abortions, two stillbirths,
and two live births with intrauterine growth restriction (birth
weight lower than the third centile for gestational age) and
mild adrenal insufficiency in both newborns. A histological
study was performed on the product of one stillbirth (patient
5) and disclosed intrauterine growth restriction associated
with marked adrenal hypoplasia.
Except for patient 7 with repeatedly high positive anti-
cardiolipin antibodies, none of the other patients who under-
went a miscarriage had significant antiphospholipid positiv-
ity.
Electrocardiograms were available for six children within
the first week of life and the mean PR interval was 88 ms
(range 80–100).
DISCUSSION
We did not observe any CHB in our series of pregnancy in
women at high risk. However, the small number of women in
each of the subgroups precludes any conclusions about the
prophylactic role of steroids in CHB. The four pregnancies
conducted under treatment with prednisone were uneventful.
By contrast, we observed an unexpectedly high rate of adverse
obstetric events in patients treated with dexamethasone,
including spontaneous abortion, stillbirth, severe intrauterine
growth restriction, and adrenal insufficiency/hypoplasia. Mis-
car riages and severe intrauterine growth restriction could not
be explained by the association with an antiphospholipid syn-
drome as no patients receiving dexamethasone had significant
antiphospholipid positivity. No other explanation (like viral
infection) could be found, leading us to suspect a relationship
with dexamethasone administration.
Accordingly, concerns have been raised about the safety of
fluorinated steroids due to concordant animal studies,
retrospective data, and randomised trials. Firstly, antenatal
dexamethasone given to promote fetal maturation is associ-
ated with diminished birth weight.
9
Secondly, brief prenatal
exposure to dexamethasone has led to the development of
hypertension, left ventricular hypertrophy, and reduced
cardiac functional reserve in adult sheep.
10
Clinically signifi-
cant left ventricular myocardial hypertrophy has been recently
reported in preterm humans neonates after an early shor t
course of dexamethasone for neonatal chronic lung disease,
11
and antenatal betamethasone treatment has been associated
with higher systolic and diastolic blood pressures in
adolescence.
12
However, the major concern is probably about the neuro-
logical effects of dexamethasone. Indeed, administration of
Table 1 Specific outcome of 13 pregnancies in seven women with anti-SSA/Ro antibodies who had previously had
fetuses with CHB
Patient
No
Current maternal
diagnosis Previous pregnancies with CHB
Corticosteroid
treatment of following
pregnancies
Outcome of following
pregnancies Sex
Gestational
age (WG)
Birth
weight (g)
1 SLE 1 CHB (death at 2 days of life) Dexamethasone (4
mg/day)
Spontaneous abortion (15 WG) – – –
Prednisone (10
mg/day)
Live birth F 40 4130
2 SLE 1 CHB (death at 6 months of life) Dexamethasone (4.5
mg/day)
Spontaneous abortion (18 WG) – – –
Dexamethasone (4.5
mg/day)
Stillbirth (24 WG) – – –
Prednisone (10
mg/day)
Live birth F 38 2680
3 Primary SS 2 CHB (pacemaker in both
cases)
Dexamethasone (4
mg/day)
Live birth (adrenal insufficiency) M 37 2140*
Dexamethasone (4
mg/day)
Live birth (adrenal insufficiency) M 37 1870*
4 Symptom free 1 CHB (stillbirth at 30 WG) None Spontaneous abortion (11 WG) – – –
None Live birth F 40 4030
5 Primary SS 1 CHB (no need of pacemaker
at 4 years)
Dexamethasone (5
mg/day)
Stillbirth (32 WG) (adrenal
hypoplasia)
–– –
6 Primary SS 1 CHB (no need of pacemaker
at 10 years)
Prednisone (10
mg/day)
Live birth F 39 2930
7 Primary SS + high
APL
1 CHB (pacemaker at 18
months)
None Spontaneous abortion (5 WG) – – –
Prednisone (10
mg/day)
Live birth M 39 3080
*Intrauterine growth restriction (birth weight lower than the third centile for gestational age).
CHB, congenital heart block; WG, weeks’ gestation; SLE, systemic lupus erythematosus; primary SS, primary Sjögren’s syndrome; APL, antiphospholipid
antibodies.
Treatment of congenital heart block 1011
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dexamethasone in high doses to pregnant rhesus monkeys
during the period corresponding to the early third trimester of
human pregnancy induced degeneration and depletion of the
hippocampal pyramidal and dentate g ranular neurones in the
fetal brain.
13
In humans, it has been suspected that fluorinated
steroids used in utero to prevent virilisation of female fetuses
affected by congenital adrenal hyperplasia induce adverse
events, including severe growth retardation and delayed
psychomotor development.
14 15
Additionally, m arkedly im-
paired growth of cerebral cortical gray matter has been
recently reported in preterm neonates after an early short
course of dexamethasone for neonatal chronic lung disease.
16
In a meta-analysis, Barrington found that postnatal pharma-
cological steroid administration for prevention or treatment of
bronchopulmonary dysplasia was associated with a dramatic
increase in neuro-developmental impairment.
17
The author
proposed to abandon its use for this indication.
17
Finally, Baud
et al found that the adjusted odds ratio of cystic periventricu-
lar leucomalacia among very premature infants was 1.5 (95%
confidence interval 0.8 to 2.9) for the group of infants whose
mothers had received dexamethasone as compared with the
group of infants whose mothers had not received a
glucocorticoid.
18
By contrast, antenatal exposure to beta-
methasone was associated with a decreased risk of cystic peri-
ventricular leucomalacia.
18
These results might be ascribed to
the sulphites used as preservatives in dexamethasone, as
emphasised by an in vitro experience on neuronal viability
after exposure to steroids.
19
In view of these results, the case of
a former child (not included in this report) of patient 2, who
was treated in utero with dexamethasone after discovery of
CHB, is relevant. This child was admitted to hospital at 6
months of age for pulmonary infection. His condition rapidly
deteriorated. Magnetic resonance imaging showed “unex-
pected” cerebral necrosis, and death occurred in the intensive
care unit without clear explanation.
In conclusion, prophylactic regimens in pregnant women
with anti-SSA/Ro antibodies should be closely evaluated. In
the absence of a prior history of CHB, the risk of CHB is low as
recently demonstrated.
2
Depending on the mother’s disease,
abstention from, or a low dose of, prednisone seems to be the
cor rect course if abnormal findings are not seen on close
echocardiographic follow up; the latter should be performed
between 16 and 24 weeks’ gestation as emphasised by Buyon
et al.
1
Optimal management of women with a past history of
CHB remains unclear as there is no convincing evidence for
the use of steroids. A multicentre prospective study would be
needed to answer this question. If steroids have to be used
because of increasing concerns, prednisone is preferable and
fluorinated steroids should be avoided. Finally, administration
of fluorinated steroids in established CHB requires close
evaluation of efficiency and fetal safety and, in accordance
with the study by Baud et al ,
18 19
betamethasone should prob-
ably be prefer red to dexamethasone for this purpose.
.....................
Authors’ affiliations
N Costedoat-Chalumeau, Z Amoura, D Le Thi Hong, B Wechsler,
D Vauthier, P Ghillani, T Papo, O Fain, L Musset, J-C Piette, Centre
Hospitalier, Universitaire Pitié-Salpêtrière, Paris, France
Correspondence to: Dr N Costedoat-Chalumeau, 47–83 Bd de l’Hôpital,
Centre Hospitalier, Universitaire Pitié-Salpêtrière, Paris 75013, France;
nathalie.costedoat@psl.ap-hop-paris.fr
Accepted 22 January 2003
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