Nitroglycerine is a standby of
cardiac medicine. But a new Canadian study suggests
the chemical may have another estimable quality —
it is a tocolytic, a drug able to retard delivery in
women heading for a premature birth. In fact, nitroglycerine
may be the first such drug to not only help women carry
their babies closer to term, but protect the fetus as
well, according to research by Queen's University's
Perinatal Research Unit at Kingston General Hospital,
published in the American Journal of Obstetrics and
Gynecology. Unlike other such drugs that have brought
no apparent improvement in neonates' health, nitroglycerine
significantly reduced neonatal morbidity as measured
by a range of serious outcomes, including perinatal
death.
THE
WEAKEST LINK
The researchers recruited 158 women at large teaching
hospitals who were already apparently in labour between
24 and 32 weeks. They were randomized to receive either
nitroglycerine through 24-hour transdermal patches,
or placebo. If regular contractions continued an hour
after the patch was applied, another was added. The
following day, the treatment was repeated, for a total
of 48 hours.
Technically, the study didn't achieve
a significant delay in delivery in the nitroglycerine
group. Among women randomized to receive the drug, delivery
came a modest seven days later than in placebo patients.
But these findings are weakened by the known tendency
to overdiagnose preterm labour. If the patients who
went on to full term are excluded from the analysis,
as having never really been in preterm labour, the prolongation
stretches to 10 days for all mothers, and a hugely significant
23 days for those in labour before 28 weeks.
This is crucial, says lead author
Dr Graeme Smith of Kingston General, because that's
the group whose babies are most at risk. "All but one
case of significant neonatal morbidity occurred in a
delivery before 28 weeks," he says.
BETTER
FOR BABY
The researchers measured morbidity using a composite
of outcomes: chronic lung disease, necrotizing enterocolitis,
significant intraventricular hemorrhage, periventricular
leukomalacia and perinatal mortality. Overall, the "composite
primary outcome", including at least one of these conditions,
occurred in three nitroglycerine-treated pregnancies,
and eleven placebo-treated pregnancies, just squeaking
in under the bar of statistical significance.
While other tocolytics have shown
comparable or better overall delays in delivery, none
has shown any ability to improve fetal health. Dr Smith
suggests two reasons for this. First, nitroglycerine
prolongs pregnancy most in the most vulnerable group,
the mothers who enter labour before 28 weeks. Secondly,
nitroglycerine may be having effects beyond its tocolytic
properties.
This could be a direct effect on
blood flow in the placenta, he suggests. "While only
minute quantities of nitroglycerine get across the placenta
to the fetus, plenty reaches the placenta and there
is some evidence of a direct effect," he says.
A
TIMING THING
Recruitment for the trial was stopped early when the
maker of the leading tocolytic in Canada, ritodrine,
withdrew its unprofitable drug from the market in 2004.
Many centres switched to off-label use of nitroglycerine,
so patients weren't keen to join a trial in which they
risked being given placebo. As a result, the researchers
were left with smaller numbers than they had hoped for.
Dr Smith says that while there's
no gold standard tocolytic in Canada, he estimates that
"about a third" of Canadian centres are now using nitroglycerine.
"Canadian doctors have never warmed to 'take-home' tocolytics
while in the US patients are often given one after being
discharged. It's a very different approach to treatment."
The Canadian Tocolysis Consensus
Conference recently agreed that there was little evidence
to support the use of any available tocolytics, because
of the lack of improvement in outcomes and the frequent
side effects. Nitroglycerine is not without side effects
either. The main complaint in the trial was headache,
but most didn't necessitate patch removal.
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