Dear Editor,
We would like to comment on the systematic review by Li et al.(1)
The use of steroid hormones in the first trimester is a serious issue as
organogenesis takes place at this time and therefore there is the
possibility of harm from not only congenital anomalies, but also
long-term, and even inter-generational effects. Anyone investigating the
use of steroid hormones in the first trimester should remember the
diethylstilbestrol legacy of devastating harm. Oestrogen
(C18H24O2) and
diethylstilbestrol
(C18H20O2) have similar
molecular composition, but their effects are poles apart. In this
review, the authors have combined progesterone with progestogens;
however they are not the same, in the same way that oestrogen and
diethylstilbestrol are not the same. Vaginal micronized progesterone,
which we used in our large and high-quality trials (the PROMISE (2) and
PRISM (3) trials), has identical molecular structure to natural
progesterone, but the other drugs included in this review do not (Table
1). We chose to study vaginal micronized progesterone, as it is
identical in structure to natural progesterone, and the available
evidence and expert opinion suggested that this is least likely to cause
harm. It is important to note that there is evidence of potential harm
from dydrogesterone, particularly congenital heart disease.(4)
The authors make a bold statement in the abstract about the effects of
dydrogesterone on live birth rate. However, they don’t fully address the
weaknesses in the evidence. Therefore, we wish to highlight the
significant deficiencies in the two trials that contributed live birth
data that led to the assertion of beneficial effects from
dydrogesterone. Both studies were single centre, open-label studies
without placebo control. El-Zibdeh et al did not randomise participants,
but instead allocated patients to dydrogesterone on Saturdays, Mondays
and Wednesdays, and to no treatment on Sundays, Tuesdays and Thursdays.
The trial by Pandian RU was not just a single-centre, but also a
single-author study, with insufficient details of the methods to assess
its quality. Thus, the effectiveness evidence from these trials cannot
be considered reliable.
Approximately 80% (4038 of 5056) of the data used in this systematic
review come from our PRISM trial.(3) The PRISM trial is a
prospectively-registered, randomised, placebo-controlled, multi-centre
trial conducted to the highest standards in the UK. The trial found a
3% increase in live birth rate, but with borderline statistical
significance (RR, 1.03; 95% CI, 1.00 to 1.07; P=0.08). A pre-specified
subgroup analysis in women with the dual risk factors of current
pregnancy bleeding and one or more previous miscarriages found a 5%
increase in live birth rate (RR, 1.09; 95% CI, 1.03-1.15; P=0.003). In
those with three or more previous miscarriages, a 15% increase in live
birth rate was observed (RR, 1.28; 95% CI, 1.08 to 1.51; P=0.004).(3,
5) No short-term safety concerns were identified. Based on these data,
our recommendation is to consider vaginal micronized progesterone for
women with early pregnancy bleeding and one or more previous
miscarriages. As for the role of dydrogesterone, we need not only
high-quality, randomised trial evidence of its effects but also credible
evidence of its safety. As dydrogesterone is a synthetic
progesterone-like drug, i.e. a progestogen but not progesterone, the
burden of proof to demonstrate short- and long-term safety rests on
those promoting this drug.